CGRP receptor antagonists

ABSTRACT

The present invention is directed to compounds of Formula I:  
                 
 
and Formula II:  
                 
 
(where variables R 1 , R 2 , R 3 , R 4 , A, B, G, J, Q, T, U, V, W, X and Y are as defined herein) useful as antagonists of CGRP receptors and useful in the treatment or prevention of diseases in which the CGRP is involved, such as headache, migraine and cluster headache. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which CGRP is involved.

BACKGROUND OF THE INVENTION

CGRP (Calcitonin Gene-Related Peptide) is a naturally occurring 37-aminoacid peptide that is generated by tissue-specific alternate processingof calcitonin messenger RNA and is widely distributed in the central andperipheral nervous system. CGRP is localized predominantly in sensoryafferent and central neurons and mediates several biological actions,including vasodilation. CGRP is expressed in alpha- and beta-forms thatvary by one and three amino acids in the rat and human, respectively.CGRP-alpha and CGRP-beta display similar biological properties. Whenreleased from the cell, CGRP initiates its biological responses bybinding to specific cell surface receptors that are predominantlycoupled to the activation of adenylyl cyclase. CGRP receptors have beenidentified and pharmacologically evaluated in several tissues and cells,including those of brain, cardiovascular, endothelial, and smooth muscleorigin.

CGRP is a potent vasodilator that has been implicated in the pathologyof cerebrovascular disorders such as migraine and cluster headache. Inclinical studies, elevated levels of CGRP in the jugular vein were foundto occur during migraine attacks (Goadsby et al., Ann. Neurol., 1990,28, 183-187). CGRP activates receptors on the smooth muscle ofintracranial vessels, leading to increased vasodilation, which isthought to be the major source of headache pain during migraine attacks(Lance, Headache Pathogenesis: Monoamines, Neuropeptides, Purines andNitric Oxide, Lippincott-Raven Publishers, 1997, 3-9). The middlemeningeal artery, the principle artery in the dura mater, is innervatedby sensory fibers from the trigeminal ganglion which contain severalneuropeptides, including CGRP. Trigeminal ganglion stimulation in thecat resulted in increased levels of CGRP, and in humans, activation ofthe trigeminal system caused facial flushing and increased levels ofCGRP in the external jugular vein (Goadsby et al., Ann. Neurol., 1988,23, 193-196). Electrical stimulation of the dura mater in rats increasedthe diameter of the middle meningeal artery, an effect that was blockedby prior administration of CGRP(8-37), a peptide CGRP antagonist(Williamson et al., Cephalalgia, 1997, 17, 525-531). Trigeminal ganglionstimulation increased facial blood flow in the rat, which was inhibitedby CGRP(8-37) (Escott et al., Brain Res. 1995, 669, 93-99). Electricalstimulation of the trigeminal ganglion in marmoset produced an increasein facial blood flow that could be blocked by the non-peptide CGRPantagonist BIBN4096BS (Doods et al., Br. J. Pharmacol., 2000, 129,420-423). Thus the vascular effects of CGRP may be attenuated, preventedor reversed by a CGRP antagonist. In recently reported clinical trials,the CGRP receptor antagonist BIBN 4096 BS was reported to be effectivein treating acute attacks of migraine (Olesen et al., N. Engl. J. Med.2004, 350:1104-1110).

CGRP-mediated vasodilation of rat middle meningeal artery was shown tosensitize neurons of the trigeminal nucleus caudalis (Williamson et al.,The CGRP Family: Calcitonin Gene-Related Peptide (CGRP), Amylin, andAdrenomedullin, Landes Bioscience, 2000, 245-247). Similarly, distentionof dural blood vessels during migraine headache may sensitize trigeminalneurons. Some of the associated symptoms of migraine, includingextra-cranial pain and facial allodynia, may be the result of sensitizedtrigeminal neurons (Burstein et al., Ann. Neurol. 2000, 47, 614-624). ACGRP antagonist may be beneficial in attenuating, preventing orreversing the effects of neuronal sensitization.

The ability of the compounds of the present invention to act as CGRPantagonists makes them useful pharmacological agents for disorders thatinvolve CGRP in humans and animals, but particularly in humans. Suchdisorders include migraine and cluster headache (Doods, Curr Opin InvesDrugs, 2001, 2 (9), 1261-1268; Edvinsson et al., Cephalalgia, 1994, 14,320-327); chronic tension type headache (Ashina et al., Neurology, 2000,14, 1335-1340); pain (Yu et al., Eur. J. Pharm., 1998, 347, 275-282);chronic pain (Hulsebosch et al., Pain, 2000, 86, 163-175); neurogenicinflammation and inflammatory pain (Holzer, Neurosci., 1988, 24,739-768; Delay-Goyet et al., Acta Physiol. Scanda. 1992, 146, 537-538;Salmon et al., Nature Neurosci., 2001, 4(4), 357-358); eye pain (May etal. Cephalalgia, 2002, 22, 195-196), tooth pain (Awawdeh et al., Int.Endocrin. J., 2002, 35, 30-36), non-insulin dependent diabetes mellitus(Molina et al., Diabetes, 1990, 39, 260-265); vascular disorders;inflammation (Zhang et al., Pain, 2001, 89, 265), arthritis, bronchialhyperreactivity, asthma, (Foster et al., Ann. NY Acad. Sci., 1992, 657,397-404; Schini et al., Am. J. Physiol., 1994, 267, H2483-H2490; Zhenget al., J. Virol., 1993, 67, 5786-5791); shock, sepsis (Beer et al.,Crit. Care Med., 2002, 30 (8), 1794-1798); opiate withdrawal syndrome(Salmon et al., Nature Neurosci., 2001, 4(4), 357-358) morphinetolerance (Menard et al., J. Neurosci., 1996, 16 (7), 2342-2351); hotflashes in men and women (Chen et al., Lancet, 1993, 342, 49; Spetz etal., J. Urology, 2001, 166, 1720-1723); allergic dermatitis (Wallengren,Contact Dermatitis, 2000, 43 (3), 137-143); psoriasis; encephalitis,brain trauma, ischaemia, stroke, epilepsy, and neurodegenerativediseases (Rohrenbeck et al., Neurobiol. of Disease 1999, 6, 15-34); skindiseases (Geppetti and Holzer, Eds., Neurogenic Inflammation, 1996, CRCPress, Boca Raton, Fla.), neurogenic cutaneous redness, skinrosaceousness and erythema; tinnitus (Herzog et al., J. MembraneBiology, 2002, 189(3), 225); inflammatory bowel disease, irritable bowelsyndrome, (Hoffman et al. Scandinavian Journal of Gastroenterology,2002, 37(4) 414-422) and cystitis. Of particular importance is the acuteor prophylactic treatment of headache, including migraine and clusterheadache.

The present invention relates to compounds that are useful as ligandsfor CGRP receptors, in particular antagonists for CGRP receptors,processes for their preparation, their use in therapy, pharmaceuticalcompositions comprising them and methods of therapy using them.

SUMMARY OF THE INVENTION

The present invention is directed to compounds of Formula I:

and Formula II:

(where variables R¹, R², R³, R⁴, A, B, G, J, Q, T, U, V, W, X and Y areas defined herein) useful as antagonists of CGRP receptors and useful inthe treatment or prevention of diseases in which the CGRP is involved,such as headache, migraine and cluster headache. The invention is alsodirected to pharmaceutical compositions comprising these compounds andthe use of these compounds and compositions in the prevention ortreatment of such diseases in which CGRP is involved.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to CGRP antagonists which includecompounds of Formula I:

wherein:

-   A is a bond, C(R²)₂, O, S(O)_(m) or NR²;-   B is (C(R²)₂)_(n);-   R¹ is selected from:    -   1) H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃₋₆        cycloalkyl, and heterocycle, unsubstituted or substituted with        one or more substituents independently selected from:        -   a) C₁₋₆ alkyl,        -   b) C₃₋₆ cycloalkyl,        -   c) aryl, unsubstituted or substituted with 1-5 substituents            where the substituents are independently selected from R⁴,        -   d) heteroaryl, unsubstituted or substituted with 1-5            substituents where the substituents are independently            selected from R⁴,        -   e) heterocycle, unsubstituted or substituted with 1-5            substituents where the substituents are independently            selected from R⁴,        -   f) (F)_(p)C-3 alkyl,        -   g) halogen,        -   h) OR⁴,        -   i) O(CH₂)_(s)OR⁴,        -   j) CO₂R⁴,        -   k) (CO)NR¹⁰R¹¹,        -   l) O(CO)NR¹⁰R¹¹,        -   m) N(R⁴)(CO)NR¹⁰R₁₁,        -   n) N(R¹⁰)(CO)R¹¹,        -   o) N(R¹⁰)(CO)OR¹¹,        -   p) SO₂NR¹⁰R¹¹,        -   q) N(R¹⁰)SO₂R¹¹,        -   r) S(O)_(m)R¹⁰,        -   s) CN,        -   t) NR¹⁰R¹¹,        -   u) N(R¹⁰)(CO)NR⁴R¹¹, and,        -   v) O(CO)R⁴;    -   2) aryl or heteroaryl, unsubstituted or substituted with one or        more substituents independently selected from:        -   a) C₁₋₆ alkyl,        -   b) C₃₋₆ cycloalkyl,        -   c) aryl, unsubstituted or substituted with 1-5 substituents            where the substituents are independently selected from R⁴,        -   d) heteroaryl, unsubstituted or substituted with 1-5            substituents where the substituents are independently            selected from R⁴,        -   e) heterocycle, unsubstituted or substituted with 1-5            substituents where the substituents are independently            selected from R⁴,        -   f) (F)_(p)C₁₋₃ alkyl,        -   g) halogen,        -   h) OR⁴,        -   i) O(CH₂)_(s)OR⁴,        -   j) CO₂R⁴,        -   k) (CO)NR¹⁰R¹¹,        -   l) O(CO)NR¹⁰R¹¹,        -   m) N(R⁴)(CO)NR¹⁰R¹¹,        -   n) N(R¹⁰)(CO)R¹¹,        -   o) N(R¹⁰)(CO)OR¹¹,        -   p) SO₂NR¹⁰R¹¹,        -   q) N(R¹⁰)SO₂R¹¹,        -   r) S(O)_(m)R¹⁰,        -   s) CN,        -   t) NR¹⁰R¹¹,        -   u) N(R¹⁰)(CO)NR⁴R¹¹, and        -   v) O(CO)R⁴;-   R² is independently selected from:    -   1) H, C₀-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃₋₆ cycloalkyl        and heterocycle, unsubstituted or substituted with one or more        substituents independently selected from:        -   a) C₁₋₆ alkyl,        -   b) C₃₋₆ cycloalkyl,        -   c) aryl, unsubstituted or substituted with 1-5 substituents            where the substituents are independently selected from R⁴,        -   d) heteroaryl, unsubstituted or substituted with 1-5            substituents where the substituents are independently            selected from R⁴,        -   e) heterocycle, unsubstituted or substituted with 1-5            substituents where the substituents are independently            selected from R⁴,        -   f) (F)_(p)C₁₋₃ alkyl,        -   g) halogen,        -   h) OR⁴,        -   i) O(CH₂)_(s)OR⁴,        -   j) CO₂R⁴,        -   k) (CO)NR¹⁰R¹¹,        -   l) O(CO)NR¹⁰R¹¹,        -   m) N(R⁴)(CO)NR¹⁰R¹¹,        -   n) N(R¹⁰)(CO)R¹¹,        -   o) N(R¹⁰)(CO)OR¹¹,        -   p) SO₂NR¹⁰R¹¹,        -   q) N(R¹⁰)SO₂R¹¹,        -   r) S(O)_(m)R¹⁰,        -   s) CN,        -   t) NR¹⁰R¹¹,        -   u) N(R¹⁰)(CO)NR⁴R¹¹, and,        -   v) O(CO)R⁴;    -   2) aryl or heteroaryl, unsubstituted or substituted with one or        more substituents independently selected from:        -   a) C₁₋₆ alkyl,        -   b) C₃₋₆ cycloalkyl,        -   c) aryl, unsubstituted or substituted with 1-5 substituents            where the substituents are independently selected from R⁴,        -   d) heteroaryl, unsubstituted or substituted with 1-5            substituents where the substituents are independently            selected from R⁴,        -   e) heterocycle, unsubstituted or substituted with 1-5            substituents where the substituents are independently            selected from R⁴,        -   f) (F)_(p)C₁₋₃ alkyl,        -   g) halogen,        -   h) OR⁴,        -   i) O(CH₂)_(s)OR⁴,        -   j) CO₂R⁴,        -   k) (CO)NR¹⁰R¹¹,        -   l) O(CO)NR¹⁰R¹¹,        -   m) N(R⁴)(CO)NR¹⁰R¹¹,        -   n) N(R¹⁰)(CO)R¹¹,        -   o) N(R¹⁰)(CO)OR¹¹,        -   p) SO₂NR¹⁰R¹¹,        -   q) N(R¹⁰)SO₂R¹¹,        -   r) S(O)_(m)R¹⁰,        -   s) CN,        -   t) NR¹⁰R¹¹,        -   u) N(R¹⁰)(CO)NR⁴R¹¹, and        -   v) O(CO)R⁴,    -   or, any two independent R² on the same or adjacent atoms may be        joined together to form a ring selected from cyclobutyl,        cyclopentenyl, cyclopentyl, cyclohexenyl, cyclohexyl, phenyl,        naphthyl, thienyl, thiazolyl, thiazolinyl, oxazolyl, oxazolinyl,        imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrimidyl,        pyrazinyl, pyrrolyl, pyrrolinyl, morpholinyl, thiomorpholine,        thiomorpholine S-oxide, thiomorpholine S-dioxide, azetidinyl,        pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl,        tetrahydropyridyl, furanyl, dihydrofuranyl, dihydropyranyl and        piperazinyl;-   R¹⁰ and R¹¹ are independently selected from: H, C₁₋₆ alkyl,    (F)_(p)C₁₋₆ alkyl, C₃₋₆ cycloalkyl, aryl, heteroaryl, and benzyl,    unsubstituted or substituted with halogen, hydroxy or C₁-C₆ alkoxy,    where R¹⁰ and R¹¹ may be joined together to form a ring selected    from: azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or    morpholinyl, which is unsubstituted or substituted with 1-5    substituents where the substituents are independently selected from    R⁴;-   R⁴ is independently selected from: H, C₁₋₆ alkyl, (F)_(p)C₁₋₆ alkyl,    C₃₋₆ cycloalkyl, aryl, heteroaryl and benzyl, unsubstituted or    substituted with halogen, hydroxy or C₁-C₆ alkoxy;-   W is O, NR⁴ or C(R⁴)₂;-   X is C or S;-   Y is O, (R⁴)₂, NCN, NSO₂CH₃, NCONH₂, or Y is O₂ when X is S;-   R⁶ is independently selected from H and:    -   a) C₁₋₆ alkyl,    -   b) C₃₋₆ cycloalkyl,    -   c) aryl, unsubstituted or substituted with 1-5 substituents        where the substituents are independently selected from R⁴,    -   d) heteroaryl, unsubstituted or substituted with 1-5        substituents where the substituents are independently selected        from R⁴,    -   e) heterocycle, unsubstituted or substituted with 1-5        substituents where the substituents are independently selected        from R⁴,    -   f) (F)_(p)C₁₃ alkyl,    -   g) halogen,    -   h) OR⁴,    -   i) O(CH₂)_(s)OR⁴,    -   j) CO₂R⁴,    -   k) (CO)NR¹⁰R¹¹,    -   l) O(CO)NR¹⁰R¹¹,    -   m) N(R⁴)(CO)NR¹⁰R¹¹,    -   n) N(R¹⁰)(CO)R¹¹,    -   o) N(R¹⁰)(CO)OR¹¹,    -   p) SO₂NR¹⁰R¹¹,    -   q) N(R¹⁰)SO₂R¹¹,    -   r) S(O)_(m)R¹⁰,    -   s) CN,    -   t) NR¹⁰R¹¹,    -   u) N(R¹⁰)(CO)NR⁴R¹¹, and    -   v) O(CO)R⁴;-   G-J is selected from: N, N—C(R⁵)₂, C═C(R⁵), C═N; C(R⁵),    C(R⁵)—C(R⁵)₂, C(R⁵)—C(R⁵)₂—C(R⁵)₂, C═C(R⁵)—C(R⁵)₂,    C(R⁵)—C(R⁵)═C(R⁵), C(R⁵)—C(R⁵)₂-N(R⁵), C═C(R⁵)—N(R⁵), C(R⁵)—C(R⁵)═N,    C(R⁵)—N(R⁵)—C(R⁵)₂, C═N—C(R⁵)₂, C(R⁵)—N═C(R⁵), C(R⁵)—N(R⁵)—N(R⁵),    C═N—N(R⁵), N—C(R⁵)₂—C(R⁵)₂, N—C(R⁵)═C(R⁵), N—C(R⁵)₂-N(R⁵),    N—C(R⁵)═N, N—N(R⁵)—C(R⁵)₂ and N—N═C(R⁵);-   Q, T, U and V are each independently a carbon atom or a nitrogen    atom wherein at least one but no more than three of Q, T, U and V    are nitrogen atoms, of which one may be optionally an N-oxide, and    wherein when any of Q, T, U, or V is a carbon atom it is    unsubstituted or substituted where the substituents are    independently selected from R⁶;-   R⁵ is independently selected from H, substituted or unsubstituted    C₁-C₃ alkyl, CN, OR⁴, N(R⁴)₂ and CO₂R⁴;-   R³ is independently selected from H, substituted or unsubstituted    C₁-C₃ alkyl, F, CN and CO₂R⁴;-   p is 0 to 2q+1, for a substituent with q carbons;-   m is 0, 1 or 2;-   n is 0 or 1;-   s is 1, 2 or 3;    and pharmaceutically acceptable salts and individual diastereomers    thereof.

Further embodiments of the invention are CGRP antagonists of Formula Iwhich include compounds of the Formula Ia:

wherein:

-   A is a bond, C(R²)₂, O, S(O)_(m) or NR²;-   B is (C(R²)₂)_(n);-   Y is O or NCN; and-   n is 0 or 1; and-   R¹, R², R⁴, W, Y, R³, G-J, Q, T, U, V and m are as defined in    Formula I;    and pharmaceutically acceptable salts and individual stereoisomers    thereof.

Still further embodiments of the invention are CGRP antagonists ofFormula I which include compounds of the Formula Ib:

wherein:

-   A is a bond, C(R²)₂, O, S(O)_(m) or NR²;-   B is (C(R²)₂)_(n);-   n is 0 or 1; and-   R¹, R², R⁴, W, R³, G-J, Q, T, U, V and m are as defined in Formula    I;    and pharmaceutically acceptable salts and individual stereoisomers    thereof.

Additional embodiments of the invention are CGRP antagonists of FormulaI which include compounds of the Formula Ic:

wherein:

-   R¹, R², R⁴, W, R³, G-J, Q, T, U, V and m are as defined in Formula    I;    and pharmaceutically acceptable salts and individual stereoisomers    thereof.

Additional embodiments of the invention are CGRP antagonists of FormulaI which also include compounds of the Formula Id:

wherein:

-   A is C(R²)₂, O, S(O)_(m) or NR²;-   R¹, R², R⁴, W, R³, G-J, Q, T, U, V and m are as defined in Formula    I;    and pharmaceutically acceptable salts and individual stereoisomers    thereof.

Additional embodiments of the invention are CGRP antagonists of FormulaI which include compounds of the Formula Ie:

wherein:

-   A is C(R²)₂, O, S(O)_(m) or NR²;-   R¹, R², R⁴, W, R³, G-J, Q, T, U, V and m are defined in Formula I;    and pharmaceutically acceptable salts and individual stereoisomers    thereof.

Further embodiments of the invention are CGRP antagonists of FormulaeIa-Ie, wherein:

-   R¹ is selected from:    -   1) H, C₁-C₆ alkyl, C₃₋₆ cycloalkyl and heterocycle,        unsubstituted or substituted with one or more substituents        independently selected from:        -   a) C₁₋₆ alkyl,        -   b) C₃₋₆ cycloalkyl,        -   c) aryl, unsubstituted or substituted with 1-5 substituents            where the substituents are independently selected from R⁴,        -   d) heteroaryl, unsubstituted or substituted with 1-5            substituents where the substituents are independently            selected from R⁴,        -   e) heterocycle, unsubstituted or substituted with 1-5            substituents where the substituents are independently            selected from R⁴,        -   f) (F)_(p)C₁₋₃ alkyl,        -   g) halogen,        -   h) OR⁴,        -   i) O(CH₂)_(s)OR⁴,        -   j) CO₂R⁴,        -   k) CN,        -   l) NR¹⁰R¹¹, and        -   m) O(CO)R⁴; and    -   2) aryl or heteroaryl, unsubstituted or substituted with one or        more substituents independently selected from:        -   a) C₁₋₆ alkyl,        -   b) C₃₋₆ cycloalkyl,        -   c) (F)_(p)C₁₋₃ alkyl,        -   d) halogen,        -   e) OR⁴,        -   f) CO₂R⁴,        -   g) (CO)NR¹⁰R¹¹,        -   h) SO₂NR¹⁰R¹¹,        -   i) N(R¹⁰)SO₂R¹¹,        -   j) S(O)_(m)R⁴,        -   k) CN,        -   l) NR¹⁰R¹¹, and,        -   m) O(CO)R⁴;-   R² is selected from:    -   1) H, C₀-C₆ alkyl, C₂-C₆ alkynyl, C₃₋₆ cycloalkyl and        heterocycle, unsubstituted or substituted with one or more        substituents independently selected from:        -   a) C₁₋₆ alkyl,        -   b) C₃₋₆ cycloalkyl,        -   c) aryl, unsubstituted or substituted with 1-5 sustituents            where the substituents are independently selected from R⁴,        -   d) heteroaryl, unsubstituted or substituted with 1-5            substituents where the substituents are independently            selected from R⁴,        -   e) heterocycle, unsubstituted or substituted with 1-5            substituents where the substituents are independently            selected from R⁴,        -   f) (F)_(p)C₁₋₃ alkyl,        -   g) halogen,        -   h) OR⁴,        -   i) O(CH₂)_(s)OR⁴,        -   j) CO₂R⁴,        -   k) S(O)_(m)R⁴,        -   l) CN,        -   m) NR¹⁰R¹¹, and        -   n) O(CO)R⁴; and    -   2) aryl or heteroaryl, unsubstituted or substituted with one        more substituents independently selected from:        -   a) C₁₋₆ alkyl,        -   b) C₃₋₆ cycloalkyl,        -   c) (F)_(p)C₁₋₃ alkyl,        -   d) halogen,        -   e) OR⁴,        -   f) CO₂R⁴,        -   g) (CO)NR¹⁰R¹¹,        -   h) SO₂NR¹⁰R¹¹,        -   i) N(R¹⁰)SO₂R¹¹,        -   j) S(O)_(m)R⁴,        -   k) CN,        -   l) NR¹⁰R¹¹, and        -   m) O(CO)R⁴,    -   or, any two independent R² on the same or adjacent atoms may be        joined together to form a ring selected from cyclobutyl,        cyclopentenyl, cyclopentyl, cyclohexenyl, cyclohexyl, phenyl,        naphthyl, thienyl, thiazolyl, thiazolinyl, oxazolyl, oxazolinyl,        imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrimidyl,        pyrazinyl, pyrrolyl, pyrrolinyl, morpholinyl, thiomorpholine,        thiomorpholine S-oxide, thiomorpholine S-dioxide, azetidinyl,        pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl,        tetrahydropyridyl, furanyl, dihydrofuranyl, dihydropyranyl and        piperazinyl;-   R¹⁰ and R¹¹ are independently selected from: H, C₁₋₆ alkyl,    (F)_(p)C₁₆ alkyl, C₃₋₆ cycloalkyl, aryl, heteroaryl and benzyl,    unsubstituted or substituted with halogen, hydroxy or C₁-C₆ alkoxy,    where R¹⁰ and R¹¹ may be joined together to form a ring selected    from: azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and    morpholinyl, which is unsubstituted or substituted with 1-5    substituents where the substituents are independently selected from    R⁴-   R⁴ is independently selected from: H, C₁₋₆ alkyl, (F)_(p)C₁₆ alkyl,    C₃₋₆ cycloalkyl, aryl, heteroaryl and benzyl, unsubstituted or    substituted with halogen, hydroxy or C₁-C₆ alkoxy;-   W is O, NR⁴ or C(R⁴)₂;-   G-J is selected from:-   N, such that when G-J is so defined the following structure forms:-   N—C(R⁵)₂, such that when G-J is so defined the following structure    forms:-   C═C(R⁵), such that when G-J is so defined the following structure    forms:-   C═N, such that when G-J is so defined the following structure forms:-   C═C(R⁵)—C(R⁵)₂, such that when G-J is so defined the following    structure forms:-   C(R⁵)—C(R⁵)═C(R⁵), such that when G-J is so defined the following    structure forms:-   N—C(R⁵)₂—C(R⁵)₂, such that when G-J is so defined the following    structure forms:-   N—C(R⁵)═C(R⁵), such that when G-J is so defined the following    structure forms:-   Q, T, U and V are each independently a carbon atom or a nitrogen    atom wherein at least one but no more than three of Q, T, U and V    are nitrogen atoms, of which one may be optionally an N-oxide, and    wherein when any of Q, T, U, or V is a carbon atom it is    unsubstituted or substituted where the substituents are    independently selected from R⁶;-   R⁶ is independently selected from H and:    -   a) C₁₋₆ alkyl,    -   b) C₃₋₆ cycloalkyl,    -   c) (F)_(p)C₁₋₃ alkyl,    -   d) halogen,    -   e) OR⁴,    -   f) CO₂R⁴,    -   g) (CO)NR¹⁰R¹¹,    -   h) SO₂NR¹⁰R¹¹,    -   i) N(R¹⁰)SO₂R¹¹,    -   j) S(O)_(m)R⁴,    -   k) CN,    -   l) NR¹⁰R¹¹ and    -   m) O(CO)R⁴; and-   R⁵ is independently selected from H, substituted or unsubstituted    C₁-C₃ alkyl, CN, OR⁴, N(R⁴)₂ and CO₂R⁴;-   R³ is independently selected from H, substituted or unsubstituted    C₁-C₃ alkyl, F, CN and CO₂R⁴;-   p is 0 to 2q+1, for a substituent with q carbons-   m is 0 to 2;-   s is 1 to 3;    and pharmaceutically acceptable salts and individual stereoisomers    thereof.

Still further embodiments of the invention are CGRP antagonists ofFormulae Ia-Ie, wherein:

-   R¹ is selected from:    -   1) H, C₁-C₆ alkyl, C₃₋₆ cycloalkyl and heterocycle,        unsubstituted or substituted with one or more substituents        independently selected from:        -   a) C₁₋₆ alkyl,        -   b) C₃₋₆ cycloalkyl,        -   c) phenyl, unsubstituted or substituted with 1-5            substituents where the substituents are independently            selected from R⁴,        -   d) heteroaryl, unsubstituted or substituted with 1-5            substituents where the substituents are independently            selected from R⁴,            -   and where heteroaryl is selected from:            -   imidazole, isoxazole, oxazole, pyrazine, pyrazole,                pyridazine, pyridine, pyrimidine, and thiazole;        -   e) heterocycle, unsubstituted or substituted with 1-5            substituents where the substituents are independently            selected from R⁴, and where heterocycle is selected from:            -   azetidine, dioxane, dioxolane, morpholine, oxetane,                piperazine, piperidine, pyrrolidine, tetrahydrofuran,                and tetrahydropyran;        -   f) (F)_(p)C₁₋₃ alkyl,        -   g) halogen,        -   h) OR⁴,        -   i) O(CH₂)_(s)OR⁴,        -   j) CO₂R⁴,        -   k) CN,        -   l) NR¹⁰R¹¹,        -   m) O(CO)R⁴;    -   2) aryl or heteroaryl, selected from:        -   phenyl, imidazole, isoxazole, oxazole, pyrazine, pyrazole,            pyridazine, pyridine, pyrimidine, and thiazole,        -   unsubstituted or substituted with one or more substituents            independently selected from:        -   a) C₁₋₆ alkyl,        -   b) C₃₋₆ cycloalkyl,        -   c) (F)_(p)C₁₋₃ alkyl,        -   d) halogen,        -   e) OR⁴,        -   f) CO₂R⁴,        -   g) (CO)NR¹⁰R¹¹,        -   h) SO₂NR¹⁰R¹¹,        -   i) N(R¹⁰)SO₂R¹¹,        -   j) S(O)_(m)R⁴,        -   k) CN,        -   l) NR¹⁰R¹¹, and        -   m) O(CO)R⁴;-   R² is selected from:    -   1) H, C₀-C₆ alkyl, C₃₋₆ cycloalkyl and heterocycle,        unsubstituted or substituted with one or more substituents        independently selected from:        -   a) C₁₋₆ alkyl,        -   b) C₃₋₆ cycloalkyl,        -   c) phenyl, unsubstituted or substituted with 1-5            substituents where the substituents are independently            selected from R⁴,        -   d) heteroaryl, unsubstituted or substituted with 1-5            substituents where the substituents are independently            selected from R⁴,            -   and where heteroaryl is selected from: benzimidazole,                benzothiophene, furan, imidazole, indole, isoxazole,                oxazole, pyrazine, pyrazole, pyridazine, pyridine,                pyrimidine, pyrrole, thiazole, thiophene, and triazole;        -   e) heterocycle, unsubstituted or substituted with 1-5            substituents where the substituents are independently            selected from R⁴, and where heterocycle is selected from:            azetidine, imidazolidine, imidazoline, isoxazoline,            isoxazolidine, morpholine, oxazoline, oxazolidine, oxetane,            pyrazolidine, pyrazoline, pyrroline, tetrahydrofuran,            tetrahydropyran, thiazoline, and thiazolidine;        -   f) (F)_(p)C₁₋₃ alkyl,        -   g) halogen,        -   h) OR⁴,        -   i) O(CH₂)_(s)OR⁴,        -   j) CO₂R⁴,        -   k) CN,        -   l) NR¹⁰R¹¹, and        -   m) O(CO)R⁴; and    -   2) aryl or heteroaryl, selected from:        -   phenyl, benzimidazole, benzothiophene, furan, imidazole,            indole, isoxazole, oxazole, pyrazine, pyrazole, pyridazine,            pyridine, pyrimidine, pyrrole, thiazole, thiophene, and            triazole;        -   unsubstituted or substituted with one or more substituents            independently selected from:        -   a) C₁₋₆ alkyl,        -   b) C₃₋₆ cycloalkyl, c) (F)_(p)C₁₋₃ alkyl,        -   d) halogen,        -   e) OR⁴,        -   f) CO₂R⁴,        -   g) (CO)NR¹⁰R¹¹,        -   h) SO₂NR¹⁰R¹¹,        -   i) N(R¹⁰)SO₂R¹¹,        -   j) S(O)_(m)R⁴,        -   k) CN,        -   l) NR¹⁰R¹¹ and        -   m) O(CO)R⁴,    -   or, any two independent R² on the same or adjacent atoms may be        joined together to form a ring selected from cyclobutyl,        cyclopentenyl, cyclopentyl, cyclohexenyl, cyclohexyl, phenyl,        naphthyl, thienyl, thiazolyl, thiazolinyl, oxazolyl, oxazolinyl,        imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrimidyl,        pyrazinyl, pyrrolyl, pyrrolinyl, morpholinyl, thiomorpholine,        thiomorpholine S-oxide, thiomorpholine S-dioxide, azetidinyl,        pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl,        tetrahydropyridyl, furanyl, dihydrofuranyl, dihydropyranyl and        piperazinyl,-   R¹⁰ and R¹¹ are independently selected from: H, C₁₋₆ alkyl,    (F)_(p)C₁₋₆ alkyl, C₃₋₆ cycloalkyl, aryl, heteroaryl and benzyl,    unsubstituted or substituted with halogen, hydroxy or C₁-C₆ alkoxy,    where R¹⁰ and R¹¹ may be joined together to form a ring selected    from: azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and    morpholinyl, which is unsubstituted or substituted with 1-5    substituents where the substituents are independently selected from    R⁴;-   R⁴ is independently selected from: H, C₁₋₆ alkyl, (F)_(p)C₁₋₆ alkyl,    C₃₋₆ cycloalkyl, aryl, heteroaryl and phenyl, unsubstituted or    substituted with hydroxy or C₁-C₆ alkoxy;-   W is NR⁴ or C(R⁴)₂;-   G-J and Q-T-U-V are as follows:-   G-J is N and Q-T-U-V is N═C(R⁶)—C(R⁶)═C(R⁶), such that when G-J and    Q-T-U-V are so defined the following structure forms:-   G-J is N and Q-T-U-V is C(R⁶)═N—C(R⁶)═C(R⁶), such that when G-J and    Q-T-U-V are so defined the following structure forms:-   G-J is N and Q-T-U-V is C(R⁶)═C(R⁶)—N═C(R⁶), such that when G-J and    Q-T-U-V are so defined the following structure forms:-   G-J is N and Q-T-U-V is C(R⁶)═C(R⁶)—C(R⁶)═N, such that when G-J and    Q-T-U-V are so defined the following structure forms:-   G-J is N and Q-T-U-V is C(R⁶)═C(R⁶)—N═N, such that when G-J and    Q-T-U-V are so defined the following structure forms:-   G-J is N and Q-T-U-V is C(R⁶)═N—C(R⁶)═N, such that when G-J and    Q-T-U-V are so defined the following structure forms:-   G-J is N and Q-T-U-V is N═C(R⁶)—C(R⁶)═N, such that when G-J and    Q-T-U-V are so defined the following structure forms:-   G-J is N—C(R⁵)₂ and Q-T-U-V is C(R⁶)═C(R⁶)—C(R⁶)═N, such that when    G-J and Q-T-U-V are so defined the following structure forms:-   G-J is N—C(R⁵)₂ and Q-T-U-V is C(R⁶)═N—C(R⁶)═C(R⁶), such that when    G-J and Q-T-U-V are so defined the following structure forms:-   G-J is C═C(R⁵) and Q-T-U-V is C(R⁶)═C(R⁶)—C(R⁶)═N, such that when    G-J and Q-T-U-V are so defined the following structure forms:-   G-J is C═C(R⁵) and Q-T-U-V is C(R⁶)═N—C(R⁶)═C(R⁶), such that when    G-J and Q-T-U-V are so defined the following structure forms:-   G-J is C═N and Q-T-U-V is C(R⁶)═C(R⁶)—C(R⁶)═N, such that when G-J    and Q-T-U-V are so defined the following structure forms:-   G-J is C═N and Q-T-U-V is C(R⁶)═N—C(R⁶)═C(R⁶), such that when G-J    and Q-T-U-V are so defined the following structure forms:-   G-J is N—C(R⁵)₂—C(R⁵)₂ and Q-T-U-V is C(R⁶)═C(R⁶)—C(R⁶)═N, such that    when G-J and Q-T-U-V are so defined the following structure forms:-   G-J is N—C(R⁵)₂—C(R⁵)₂ and Q-T-U-V is C(R⁶)═N—C(R⁶)═C(R⁶), such that    when G-J and Q-T-U-V are so defined the following structure forms:-   R⁶ is independently selected from H and:    -   a) C₁₋₆ alkyl,    -   b) C₃₋₆ cycloalkyl,    -   c) (F)_(p)C₁₋₃ alkyl,    -   d) halogen,    -   e) OR⁴,    -   f) CO₂R⁴,    -   g) (CO)NR¹⁰R¹¹,    -   h) SO₂NR¹⁰R¹¹,    -   i) N(R¹⁰)SO₂R¹¹,    -   j) S(O)_(m)R⁴,    -   k) CN,    -   l) NR¹⁰R¹¹, and    -   m) O(CO)R⁴;-   R⁵ is independently selected from H, substituted or unsubstituted    C₁-C₃ alkyl, CN, OR⁴, N(R⁴)₂ and CO₂R⁴;-   R³ is independently selected from H, substituted or unsubstituted    C₁-C₃ alkyl, F, CN and CO₂R⁴;-   p is 0 to 2q+1, for a substituent with q carbons-   m is 0 to 2;-   s is 1 to 3;    and pharmaceutically acceptable salts and individual stereoisomers    thereof

Another embodiment of the invention includes CGRP antagonists whichinclude compounds of Formula II:

wherein:

-   B, G, J, Q, T, U, V, W, X, Y, R¹, R², R³ and R⁴ are as defined in    Formula I, and pharmaceutically acceptable salts and individual    diastereomers thereof.

It is to be understood that where one or more of the above recitedstructures or substructures recite multiple substituents having the samedesignation each such variable may be the same or different from eachsimilarly designated variable. For example, R² is recited four times inFormula I, and each R² in Formula I may independently be any of thesubstructures defined under R². The invention is not limited tostructures and substructures wherein each R² must be the same for agiven structure. The same is true with respect to any variable appearingmultiple time in a structure or substructure.

The compounds of the present invention may contain one or moreasymmetric centers and can thus occur as racemates and racemic mixtures,single enantiomers, diastereomeric mixtures and individualdiastereomers. Additional asymmetric centers may be present dependingupon the nature of the various substituents on the molecule. Each suchasymmetric center will independently produce two optical isomers and itis intended that all of the possible optical isomers and diastereomersin mixtures and as pure or partially purified compounds are includedwithin the ambit of this invention. The present invention is meant tocomprehend all such isomeric forms of these compounds.

Some of the compounds described herein contain olefinic double bonds,and unless specified otherwise, are meant to include both E and Zgeometric isomers.

The independent syntheses of these diastereomers or theirchromatographic separations may be achieved as known in the art byappropriate modification of the methodology disclosed herein. Theirabsolute stereochemistry may be determined by the x-ray crystallographyof crystalline products or crystalline intermediates which arederivatized, if necessary, with a reagent containing an asymmetriccenter of known absolute configuration.

If desired, racemic mixtures of the compounds may be separated so thatthe individual enantiomers are isolated. The separation can be carriedout by methods well known in the art, such as the coupling of a racemicmixture of compounds to an enantiomerically pure compound to form adiastereomeric mixture, followed by separation of the individualdiastereomers by standard methods, such as fractional crystallization orchromatography. The coupling reaction is often the formation of saltsusing an enantiomerically pure acid or base. The diasteromericderivatives may then be converted to the pure enantiomers by cleavage ofthe added chiral residue. The racemic mixture of the compounds can alsobe separated directly by chromatographic methods utilizing chiralstationary phases, which methods are well known in the art.

Alternatively, any enantiomer of a compound may be obtained bystereoselective synthesis using optically pure starting materials orreagents of known configuration by methods well known in the art.

As will be appreciated by those of skill in the art, not all of the R¹⁰and R¹¹ substituents are capable of forming a ring structure. Moreover,even those substituents capable of ring formation may or may not form aring structure.

Also as appreciated by those of skill in the art, halo or halogen asused herein are intended to include chloro, fluoro, bromo and iodo.

As used herein, “alkyl” is intended to mean linear, branched and cyclicstructures having no double or triple bonds. Thus C₁₋₆alkyl is definedto identify the group as having 1, 2, 3, 4, 5 or 6 carbons in a linearor branched arrangement, such that C₁₋₆alkyl specifically includesmethyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl,pentyl and hexyl. “Cycloalkyl” is an alkyl, part or all of which whichforms a ring of three or more atoms. C₀ or C₀alkyl is defined toidentify the presence of a direct covalent bond.

The term “alkenyl” means linear or branched structures and combinationsthereof, of the indicated number of carbon atoms, having at least onecarbon-to-carbon double bond, wherein hydrogen may be replaced by anadditional carbon-to-carbon double bond. C₂₋₆alkenyl, for example,includes ethenyl, propenyl, 1-methylethenyl, butenyl and the like.

The term “alkynyl” means linear or branched structures and combinationsthereof, of the indicated number of carbon atoms, having at least onecarbon-to-carbon triple bond. Thus C₂₋₆alkynyl is defined to identifythe group as having 2, 3, 4, 5 or 6 carbons in a linear or branchedarrangement, such that C₂₋₆alkynyl specifically includes 2-hexynyl and2-pentynyl.

As used herein, “aryl” is intended to mean any stable monocyclic orbicyclic carbon ring of up to 7 members in each ring, wherein at leastone ring is aromatic. Examples of such aryl elements include phenyl,napthyl, tetrahydronapthyl, indanyl, or biphenyl.

The term “heterocycle” or “heterocyclic”, as used herein except wherenoted, represents a stable 5- to 7-membered monocyclic- or stable 8- to11-membered bicyclic heterocyclic ring system which is either saturatedor unsaturated, and which consists of carbon atoms and from one to fourheteroatoms selected from the group consisting of N, O and S, andwherein the nitrogen and sulfur heteroatoms may optionally be oxidized,and the nitrogen heteroatom may optionally be quaternized, and includingany bicyclic group in which any of the above-defined heterocyclic ringsis fused to a benzene ring. The heterocyclic ring may be attached at anyheteroatom or carbon atom which results in the creation of a stablestructure. Examples of such heterocyclic groups include, but are notlimited to, azetidine, chroman, dihydrofuran, dihydropyran, dioxane,dioxolane, hexahydroazepine, imidazolidine, imidazolidinone,imidazoline, imidazolinone, indoline, isochroman, isoindoline,isothiazoline, isothiazolidine, isoxazoline, isoxazolidine, morpholine,morpholinone, oxazoline, oxazolidine, oxazolidinone, oxetane,2-oxohexahydroazepin, 2-oxopiperazine, 2-oxopiperidine,2-oxopyrrolidine, piperazine, piperidine, pyran, pyrazolidine,pyrazoline, pyrrolidine, pyrroline, quinuclidine, tetrahydrofuran,tetrahydropyran, thiamorpholine, thiazoline, thiazolidine,thiomorpholine and N-oxides thereof.

The term “heteroaryl”, as used herein except where noted, represents astable 5- to 7-membered monocyclic- or stable 9- to 10-membered fusedbicyclic heterocyclic ring system which contains an aromatic ring, anyring of which may be saturated, such as piperidinyl, partiallysaturated, or unsaturated, such as pyridinyl, and which consists ofcarbon atoms and from one to four heteroatoms selected from the groupconsisting of N, O and S, and wherein the nitrogen and sulfurheteroatoms may optionally be oxidized, and the nitrogen heteroatom mayoptionally be quaternized, and including any bicyclic group in which anyof the above-defined heterocyclic rings is fused to a benzene ring. Theheterocyclic ring may be attached at any heteroatom or carbon atom whichresults in the creation of a stable structure. Examples of suchheteroaryl groups include, but are not limited to, benzimidazole,benzisothiazole, benzisoxazole, benzofuran, benzothiazole,benzothiophene, benzotriazole, benzoxazole, carboline, cinnoline, furan,furazan, imidazole, indazole, indole, indolizine, isoquinoline,isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, phthalazine,pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine,pyrimidine, pyrrole, quinazoline, quinoline, quinoxaline, tetrazole,thiadiazole, thiazole, thiophene, triazine, triazole, and N-oxidesthereof.

The term “alkoxy,” as in C₁-C₆ alkoxy, is intended to refer to includealkoxy groups of from 1 to 6 carbon atoms of a straight, branched andcyclic configuration. Examples include methoxy, ethoxy, propoxy,isopropoxy, cyclopropyloxy, cyclohexyloxy and the like.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativeswherein the parent compound is modified by making acid or base saltsthereof. Examples of pharmaceutically acceptable salts include, but arenot limited to, mineral or organic acid salts of basic residues such asamines; alkali or organic salts of acidic residues such as carboxylicacids; and the like. The pharmaceutically acceptable salts include theconventional non-toxic salts or the quaternary ammonium salts of theparent compound formed, for example, from non-toxic inorganic or organicacids. For example, such conventional non-toxic salts include thosederived from inorganic acids such as hydrochloric, hydrobromic,sulfuric, sulfamic, phosphoric, nitric and the like; and the saltsprepared from organic acids such as acetic, propionic, succinic,glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic,maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic,sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic,ethane disulfonic, oxalic, isethionic, and the like.

The number of certain variables present in certain instances is definedin terms of the number of carbons present. For example, variable “p” isoccasionally defined as follows: “p is 0 to 2q+1, for a substituent withq carbons”. Where the substituent is “(F)_(p)C₁₋₃ alkyl” this means thatwhen there is one carbon, there are 2(1)+1=3 fluorines. When there aretwo carbons, there are 2(2)+1=5 fluorines, and when thre are threecarbons there are 2(3)=1=7 fluorines.

When variables G and J are presented or depicted as “G-J” this indicatesthat G and J together represent a particular moiety. G-J may represent asingle ring atom or various arrangements of multiple ring atoms. Forinstance, G-J is at times herein defined as the single ring atom N, andis at other times defined as multiple ring atoms C═C(R⁵), C═N, and soforth.

Similarly, when variables Q, T, U and V are presented or depicted as“Q-T-U-V” this indicates that these variables together represent aparticular moiety. Here, Q-T-U-V may represent various arrangements ofmultiple ring atoms, for instance N═C(R⁶)—C(R⁶)═C(R⁶),C(R⁶)═N—C(R⁶)═C(R⁶) and C(R⁶)═C(R⁶)—N═C(R⁶), among others.

When the compound of the present invention is basic, salts may beprepared from pharmaceutically acceptable non-toxic acids, includinginorganic and organic acids. Such acids include acetic, benzenesulfonic,benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic,glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic,mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic,phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, andthe like. In one aspect of the invention the salts are citric,hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, fumaric, andtartaric acids. It will be understood that, as used herein, referencesto the compounds of Formula I are meant to also include thepharmaceutically acceptable salts.

Exemplifying the invention is the use of the compounds disclosed in theExamples and herein. Specific compounds within the present inventioninclude a compound which selected from the group consisting of thecompounds disclosed in the following Examples and pharmaceuticallyacceptable salts thereof and individual diastereomers thereof.

The subject compounds are useful in a method of antagonism of CGRPreceptors in a patient such as a mammal in need of such antagonismcomprising the administration of an effective amount of the compound.The present invention is directed to the use of the compounds disclosedherein as antagonists of CGRP receptors. In addition to primates,especially humans, a variety of other mammals can be treated accordingto the method of the present invention.

Another embodiment of the present invention is directed to a method forthe treatment, control, amelioration, or reduction of risk of a diseaseor disorder in which the CGRP receptor is involved in a patient thatcomprises administering to the patient a therapeutically effectiveamount of a compound that is an antagonist of CGRP receptors.

The present invention is further directed to a method for themanufacture of a medicament for antagonism of CGRP receptors activity inhumans and animals comprising combining a compound of the presentinvention with a pharmaceutical carrier or diluent.

The subject treated in the present methods is generally a mammal, forexample a human being, male or female, in whom antagonism of CGRPreceptor activity is desired. The term “therapeutically effectiveamount” means the amount of the subject compound that will elicit thebiological or medical response of a tissue, system, animal or human thatis being sought by the researcher, veterinarian, medical doctor or otherclinician. As used herein, the term “treatment” refers both to thetreatment and to the prevention or prophylactic therapy of the mentionedconditions, particularly in a patient who is predisposed to such diseaseor disorder.

The term “composition” as used herein is intended to encompass a productcomprising the specified ingredients in the specified amounts, as wellas any product which results, directly or indirectly, from combinationof the specified ingredients in the specified amounts. Such term inrelation to pharmaceutical composition, is intended to encompass aproduct comprising the active ingredient(s), and the inert ingredient(s)that make up the carrier, as well as any product which results, directlyor indirectly, from combination, complexation or aggregation of any twoor more of the ingredients, or from dissociation of one or more of theingredients, or from other types of reactions or interactions of one ormore of the ingredients. Accordingly, the pharmaceutical compositions ofthe present invention encompass any composition made by admixing acompound of the present invention and a pharmaceutically acceptablecarrier. By “pharmaceutically acceptable” it is meant the carrier,diluent or excipient must be compatible with the other ingredients ofthe formulation and not deleterious to the recipient thereof.

The terms “administration of” and or “administering a” compound shouldbe understood to mean providing a compound of the invention or a prodrugof a compound of the invention to the individual in need of treatment.

The utility of the compounds in accordance with the present invention asantagonists of CGRP receptor activity may be demonstrated by methodologyknown in the art. Inhibition of the binding of ¹²⁵I-CGRP to receptorsand functional antagonism of CGRP receptors were determined as follows:

NATIVE RECEPTOR BINDING ASSAY: The binding of ¹²⁵I-CGRP to receptors inSK-N-MC cell membranes was carried out essentially as described(Edvinsson et al. (2001) Eur. J. Pharmacol. 415, 39-44). Briefly,membranes (25 μg) were incubated in 1 mL of binding buffer [10 mM HEPES,pH 7.4, 5 mM MgCl₂ and 0.2% bovine serum albumin (BSA)] containing 10 pM¹²⁵I-CGRP andantagonist. After incubation at room temperature for 3 h,the assay was terminated by filtration through GFB glass fibre filterplates (Millipore) that had been blocked with 0.5% polyethyleneimine for3 h. The filters were washed three times with ice-cold assay buffer,then the plates were air dried. Scintillation fluid (50 μL) was addedand the radioactivity was counted on a Topcount (Packard Instrument).Data analysis was carried out by using Prism and the K_(i) wasdetermined by using the Cheng-Prusoff equation (Cheng & Prusoff (1973)Biochem. Pharmacol. 22, 3099-3108).

NATIVE RECEPTOR FUNCTIONAL ASSAY: SK-N-MC cells were grown in minimalessential medium (MEM) supplemented with 10% fetal bovine serum, 2 mML-glutamine, 0.1 mM non-essential amino acids, 1 mM sodium pyruvate, 100units/mL penicillin and 100 μg/ml streptomycin at 37° C., 95% humidity,and 5% CO₂. For cAMP assays, cells were plated at 5×10⁵ cells/well in96-well poly-D-lysine-coated plates (Becton-Dickinson) and cultured for˜18 h before assay. Cells were washed with phosphate-buffered saline(PBS, Sigma) then pre-incubated with 300 μM isobutylmethylxanthine inserum-free MEM for 30 min at 37° C. Antagonist was added and the cellswere incubated for 10 min before the addition of CGRP. The incubationwas continued for another 4 min, then the cells were washed with PBS andprocessed for cAMP determination according to the manufacturer'srecommended protocol. Maximal stimulation over basal was defined byusing 100 nM CGRP. Dose-response curves were generated by using Prism.Dose-ratios (DR) were calculated and used to construct full Schild plots(Arunlakshana & Schild (1959) Br. J. Pharmacol. 14, 48-58).

RECOMBINANT RECEPTOR: Human CRLR (Genbank accession number L76380) wassubcloned into the expression vector pIREShyg2 (BD Biosciences Clontech)as a 5′NheI and 3′ PmeI fragment. Human RAMP1 (Genbank accession numberAJ001014) was subcloned into the expression vector pIRESpuro2 (BDBiosciences Clontech) as a 5′NheI and 3′NotI fragment. 293 cells (humanembryonic kidney cells; ATCC #CRL-1573) were cultured in DMEM with 4.5g/L glucose, 1 mM sodium pyruvate and 2 mM glutamine supplemented with10% fetal bovine serum (FBS), 100 units/mL penicillin and 100 ug/mlstreptomycin, and maintained at 37° C. and 95% humidity. Cells weresubcultured by treatment with 0.25% trypsin with 0.1% EDTA in HBSS.Stable cell line generation was accomplished by co-transfecting 10 ug ofDNA with 30 ug Lipofectamine 2000 (Invitrogen) in 75 cm² flasks. CRLRand RAMP1 expression constructs were co-transfected in equal amounts.Twenty-four hours after transfection the cells were split 1:5 andselective medium (growth medium+300 ug/mL hygromycin and 1 ug/mLpuromycin) was added the following day. A clonal cell line was generatedby single cell deposition utilizing a FACS Vantage SE (BectonDickinson). Growth medium was adjusted to 150 ug/ml hygromycin and 0.5ug/mL puromycin for cell propagation.

RECOMBINANT RECEPTOR BINDING ASSAY: Cells expressing recombinant humanCRLR/RAMP₁ were washed with PBS and harvested in harvest buffercontaining 50 mM HEPES, 1 mM EDTA and Complete protease inhibitors(Roche). The cell suspension was disrupted with a laboratory homogenizerand centrifuged at 48,000 g to isolate membranes. The pellets wereresuspended in harvest buffer plus 250 mM sucrose and stored at −70° C.For binding assays, 10 ug of membranes were incubated in 1 mL bindingbuffer (10 mM HEPES, pH 7.4, 5 mM MgCl₂, and 0.2% BSA) for 3 hours atroom temperature containing 10 pM ¹²⁵I-hCGRP (Amersham Biosciences) andinhibitor. The assay was terminated by filtration through 96-well GFBglass fiber filter plates (Millipore) that had been blocked with 0.05%polyethyleneimine. The filters were washed 3 times with ice-cold assaybuffer (10 mM HEPES, pH 7.4). Scintillation fluid was added and theplates were counted on a Topcount (Packard). Non-specific binding wasdetermined and the data analysis was carried out with the apparentdissociation constant (K_(i)) determined by using a non-linear leastsquares fitting the bound CPM data to the equation below:$Y_{obsd} = \frac{\begin{matrix}{{\left( {Y_{\max} - Y_{\min}} \right)\left( {{\%\quad I_{\max}} - {\%_{Imin}/100}} \right)} +} \\{Y_{\min} + {\left( {Y_{\max} - Y_{\min}} \right)\left( {100 - {\%\quad{I_{\max}/100}}} \right)}}\end{matrix}}{1 + \left( {\lbrack{Drug}\rbrack/{K_{i}\left( {1 + {\lbrack{Radiolabel}\rbrack/K_{d}}} \right)}^{nH}} \right.}$Where Y is observed CPM bound, Ymax is total bound counts, Y min is nonspecific bound counts, (Y max−Y min) is specific bound counts, % I maxis the maximum percent inhibition, % I min is the minimum percentinhibition, radiolabel is the probe, and the K_(d) is the apparentdissociation constant for the radioligand for the receptor as determinedby Hot saturation experiments.

RECOMBINANT RECEPTOR FUNCTIONAL ASSAY: Cells were plated in completegrowth medium at 85,000 cells/well in 96-well poly-D-lysine coatedplates (Corning) and cultured for ˜19 h before assay. Cells were washedwith PBS and then incubated with inhibitor for 30 min at 37° C. and 95%humidity in Cellgro Complete Serum-Free/Low-Protein medium (Mediatech,Inc.) with L-glutamine and 1 g/L BSA. Isobutyl-methylxanthine was addedto the cells at a concentration of 300 uM and incubated for 30 min at37° C. Human α-CGRP was added to the cells at a concentration of 0.3 nMand allowed to incubate at 37° C. for 5 min. After α-CGRP stimulationthe cells were washed with PBS and processed for cAMP determinationutilizing the two-stage assay procedure according to the manufacturer'srecommended protocol (cAMP SPA direct screening assay system; RPA 559;Amersham Biosciences). Dose response curves were plotted and IC₅₀ valuesdetermined from a 4-parameter logistic fit as defined by the equationy=((a−d)/(1+(x/c)b)+d, where y=response, x=dose, a=max response, d=minresponse, c=inflection point and b=slope.

In particular, the compounds of the following examples had activity asantagonists of the CGRP receptor in the aforementioned assays, generallywith a K_(i) or IC₅₀ value of less than about 50 μM. Such a result isindicative of the intrinsic activity of the compounds in use asantagonists of CGRP receptors.

The ability of the compounds of the present invention to act as CGRPantagonists makes them useful pharmacological agents for disorders thatinvolve CGRP in humans and animals, but particularly in humans.

The compounds of the present invention have utility in treating,preventing, ameliorating, controlling or reducing the risk of one ormore of the following conditions or diseases: headache; migraine;cluster headache; chronic tension type headache; pain; chronic pain;neurogenic inflammation and inflammatory pain; neuropathic pain; eyepain; tooth pain; diabetes; non-insulin dependent diabetes mellitus;vascular disorders; inflammation; arthritis; bronchial hyperreactivity,asthma; shock; sepsis; opiate withdrawal syndrome; morphine tolerance;hot flashes in men and women; allergic dermatitis; encephalitis; braintrauma; epilepsy; neurodegenerative diseases; skin diseases; neurogeniccutaneous redness, skin rosaceousness and erythema; tinnitus;inflammatory bowel disease, irritable bowel syndrome, cystitis; andother conditions that may be treated or prevented by antagonism of CGRPreceptors. Of particular importance is the acute or prophylactictreatment of headache, including migraine and cluster headache.

The subject compounds are further useful in a method for the prevention,treatment, control, amelioration, or reduction of risk of the diseases,disorders and conditions noted herein.

The subject compounds are further useful in a method for the prevention,treatment, control, amelioration, or reduction of risk of theaforementioned diseases, disorders and conditions in combination withother agents.

The compounds of the present invention may be used in combination withone or more other drugs in the treatment, prevention, control,amelioration, or reduction of risk of diseases or conditions for whichcompounds of Formula I or the other drugs may have utility, where thecombination of the drugs together are safer or more effective thaneither drug alone. Such other drug(s) may be administered, by a routeand in an amount commonly used therefor, contemporaneously orsequentially with a compound of Formula I. When a compound of Formula Iis used contemporaneously with one or more other drugs, a pharmaceuticalcomposition in unit dosage form containing such other drugs and thecompound of Formula I is preferred. However, the combination therapy mayalso include therapies in which the compound of Formula I and one ormore other drugs are administered on different overlapping schedules. Itis also contemplated that when used in combination with one or moreother active ingredients, the compounds of the present invention and theother active ingredients may be used in lower doses than when each isused singly. Accordingly, the pharmaceutical compositions of the presentinvention include those that contain one or more other activeingredients, in addition to a compound of Formula I.

For example, the present compounds may be used in conjunction with ananti-inflammatory or analgesic agent or an anti-migraine agent, such asan ergotamine or 5-HT₁ agonists, especially a 5-HT_(1B/1D) agonist, forexample sumatriptan, naratriptan, zolmitriptan, eletriptan, almotriptan,frovatriptan, donitriptan, and rizatriptan; a cyclooxygenase inhibitor,such as a selective cyclooxygenase-2 inhibitor, for example rofecoxib,etoricoxib, celecoxib, valdecoxib or paracoxib; a non-steroidalanti-inflammatory agent or a cytokine-suppressing anti-inflammatoryagent, for example with a compound such as aspirin, ibuprofen,ketoprofen, fenoprofen, naproxen, indomethacin, sulindac, meloxicam,piroxicam, tenoxicam, lomoxicam, ketorolac, etodolac, mefenamic acid,meclofenamic acid, flufenamic acid, tolfenamic acid, diclofenac,oxaprozin, apazone, nimesulide, nabumetone, tenidap, etanercept,tolmetin, phenylbutazone, oxyphenbutazone, diflunisal, salsalate,olsalazine or sulfasalazine and the like; or a steroidal analgesic.Similarly, the instant compounds may be administered with a painreliever such as acetaminophen, phenacetin, codeine, fentanyl,sufentanil, methadone, acetyl methadol, buprenorphine or morphine.

Additionally, the present compounds may be used in conjunction with aninterleukin inhibitor, such as an interleukin-1 inhibitor; an NK-1receptor antagonist, for example aprepitant; an NMDA antagonist; an NR2Bantagonist; a bradykinin-1 receptor antagonist; an adenosine A1 receptoragonist; a sodium channel blocker, for example lamotrigine; an opiateagonist such as levomethadyl acetate or methadyl acetate; a lipoxygenaseinhibitor, such as an inhibitor of 5-lipoxygenase; an alpha receptorantagonist, for example indoramin; an alpha receptor agonist; avanilloid receptor antagonist; an mGluR5 agonist, antagonist orpotentiator; a GABA A receptor modulator, for example acamprosatecalcium; nicotinic antagonists or agonists including nicotine;muscarinic agonists or antagonists; a selective serotonin reuptakeinhibitor, for example fluoxetine, paroxetine, sertraline, duloxetine,escitalopram, or citalopram; a tricyclic antidepressant, for exampleamitriptyline, doxepin, protriptyline, desipramine, trimipramine, orimipramine; a leukotriene antagonist, for example montelukast orzafirlukast; an inhibitor of nitric oxide or an inhibitor of thesynthesis of nitric oxide.

Also, the present compounds may be used in conjunction with ergotalkaloids, for example ergotamine, ergonovine, ergonovine,methylergonovine, metergoline, ergoloid mesylates, dihydroergotamine,dihydroergocomine, dihydroergocristine, dihydroergocryptine,dihydro-I-ergocryptine, dihydro-

-ergocryptine, ergotoxine, ergocomine, ergocristine, ergocryptine,I-ergocryptine,

-ergocryptine, ergosine, ergostane, bromocriptine, or methysergide.

Additionally, the present compounds may be used in conjunction with abeta-adrenergic antagonist such as timolol, propanolol, atenolol, ornadolol, and the like; a MAO inhibitor, for example phenelzine; acalcium channel blocker, for example flunarizine, nimodipine,lomerizine, verapamil, nifedipine, prochlorperazine or gabapentin;neuroleptics such as olanzapine and quetiapine; an anticonvulsant suchas topiramate, zonisamide, tonabersat, carabersat or divalproex sodium;an angiotensin II antagonist, for example losartan and candesartancilexetil; an angiotensin converting enzyme inhibitor such aslisinopril; or botulinum toxin type A.

The present compounds may be used in conjunction with a potentiator suchas caffeine, an H2-antagonist, simethicone, aluminum or magnesiumhydroxide; a decongestant such as phenylephrine, phenylpropanolamine,pseudoephedrine, oxymetazoline, epinephrine, naphazoline,xylometazoline, propylhexedrine, or levo-desoxy-ephedrine; anantitussive such as codeine, hydrocodone, caramiphen, carbetapentane, ordextromethorphan; a diuretic; a prokinetic agent such as metoclopramideor domperidone, and a sedating or non-sedating antihistamine.

In a particularly preferred embodiment the present compounds are used inconjunction with an anti-migraine agent, such as: an ergotamine; a 5-HT₁agonist, especially a 5-HT_(1B/1D) agonist, in particular, sumatriptan,naratriptan, zolmitriptan, eletriptan, almotriptan, frovatriptan,donitriptan and rizatriptan; and a cyclooxygenase inhibitor, such as aselective cyclooxygenase-2 inhibitor, in particular, rofecoxib,etoricoxib, celecoxib, meloxicam, valdecoxib or paracoxib.

The above combinations include combinations of a compound of the presentinvention not only with one other active compound, but also with two ormore other active compounds. Likewise, compounds of the presentinvention may be used in combination with other drugs that are used inthe prevention, treatment, control, amelioration, or reduction of riskof the diseases or conditions for which compounds of the presentinvention are useful. Such other drugs may be administered, by a routeand in an amount commonly used therefor, contemporaneously orsequentially with a compound of the present invention. When a compoundof the present invention is used contemporaneously with one or moreother drugs, a pharmaceutical composition containing such other drugs inaddition to the compound of the present invention is preferred.Accordingly, the pharmaceutical compositions of the present inventioninclude those that also contain one or more other active ingredients, inaddition to a compound of the present invention.

The weight ratio of the compound of the compound of the presentinvention to the other active ingredient(s) may be varied and willdepend upon the effective dose of each ingredient. Generally, aneffective dose of each will be used. Thus, for example, when a compoundof the present invention is combined with another agent, the weightratio of the compound of the present invention to the other agent willgenerally range from about 1000:1 to about 1:1000, or from about 200:1to about 1:200. Combinations of a compound of the present invention andother active ingredients will generally also be within theaforementioned range, but in each case, an effective dose of each activeingredient should be used.

In such combinations the compound of the present invention and otheractive agents may be administered separately or in conjunction. Inaddition, the administration of one element may be prior to, concurrentto, or subsequent to the administration of other agent(s), and via thesame or different routes of administration.

The compounds of the present invention may be administered by oral,parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV,intracisternal injection or infusion, subcutaneous injection, orimplant), by inhalation spray, nasal, vaginal, rectal, sublingual, ortopical routes of administration and may be formulated, alone ortogether, in suitable dosage unit formulations containing conventionalnon-toxic pharmaceutically acceptable carriers, adjuvants and vehiclesappropriate for each route of administration. In addition to thetreatment of warm-blooded animals the compounds of the invention areeffective for use in humans.

The pharmaceutical compositions for the administration of the compoundsof this invention may conveniently be presented in dosage unit form andmay be prepared by any of the methods well known in the art of pharmacy.All methods include the step of bringing the active ingredient intoassociation with the carrier which constitutes one or more accessoryingredients. In general, the pharmaceutical compositions are prepared byuniformly and intimately bringing the active ingredient into associationwith a liquid carrier or a finely divided solid carrier or both, andthen, if necessary, shaping the product into the desired formulation. Inthe pharmaceutical composition the active compound is included in anamount sufficient to produce the desired effect upon the process orcondition of diseases. As used herein, the term “composition” isintended to encompass a product comprising the specified ingredients inthe specified amounts, as well as any product which results, directly orindirectly, from combination of the specified ingredients in thespecified amounts.

The pharmaceutical compositions containing the active ingredient may bein a form suitable for oral use, for example, as tablets, troches,lozenges, aqueous or oily suspensions, dispersible powders or granules,emulsions, hard or soft capsules, or syrups or elixirs. Compositionsintended for oral use may be prepared according to any method known tothe art for the manufacture of pharmaceutical compositions and suchcompositions may contain one or more agents selected from the groupconsisting of sweetening agents, flavoring agents, coloring agents andpreserving agents in order to provide pharmaceutically elegant andpalatable preparations. Tablets contain the active ingredient inadmixture with non-toxic pharmaceutically acceptable excipients whichare suitable for the manufacture of tablets. These excipients may be forexample, inert diluents, such as calcium carbonate, sodium carbonate,lactose, calcium phosphate or sodium phosphate; granulating anddisintegrating agents, for example, corn starch, or alginic acid;binding agents, for example starch, gelatin or acacia; and lubricatingagents, for example magnesium stearate, stearic acid or talc. Thetablets may be uncoated or they may be coated by known techniques todelay disintegration and absorption in the gastrointestinal tract andthereby provide a sustained action over a longer period. For example, atime delay material such as glyceryl monostearate or glyceryl distearatemay be employed. They may also be coated by the techniques described inthe U.S. Pat. Nos. 4,256,108; 4,166,452; and 4,265,874 to form osmotictherapeutic tablets for control release. Oral tablets may also beformulated for immediate release, such as fast melt tablets or wafers,rapid dissolve tablets or fast dissolve films.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose,sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl, p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative and flavoring and coloringagents.

The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleagenous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally-acceptable diluent orsolvent, for example as a solution in 1,3-butane diol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

The compounds of the present invention may also be administered in theform of suppositories for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient which is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials are cocoa butter and polyethyleneglycols.

For topical use, creams, ointments, jellies, solutions or suspensions,etc., containing the compounds of the present invention are employed.Similarly, transdermal patches may also be used for topicaladministration.

The pharmaceutical composition and method of the present invention mayfurther comprise other therapeutically active compounds as noted hereinwhich are usually applied in the treatment of the above mentionedpathological conditions.

In the treatment, prevention, control, amelioration, or reduction ofrisk of conditions which require antagonism of CGRP receptor activity anappropriate dosage level will generally be about 0.01 to 500 mg per kgpatient body weight per day which can be administered in single ormultiple doses. A suitable dosage level may be about 0.01 to 250 mg/kgper day, about 0.05 to 100 mg/kg per day, or about 0.1 to 50 mg/kg perday. Within this range the dosage may be 0.05 to 0.5, 0.5 to 5 or 5 to50 mg/kg per day. For oral administration, the compositions may beprovided in the form of tablets containing 1.0 to 1000 milligrams of theactive ingredient, particularly 1.0, 5.0, 10.0, 15.0. 20.0, 25.0, 50.0,75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0,800.0, 900.0, and 1000.0 milligrams of the active ingredient for thesymptomatic adjustment of the dosage to the patient to be treated. Thecompounds may be administered on a regimen of 1 to 4 times per day, ormay be administered once or twice per day.

When treating, preventing, controlling, ameliorating, or reducing therisk of headache, migraine, cluster headache, or other diseases forwhich compounds of the present invention are indicated, generallysatisfactory results are obtained when the compounds of the presentinvention are administered at a daily dosage of from about 0.1 milligramto about 100 milligram per kilogram of animal body weight, given as asingle daily dose or in divided doses two to six times a day, or insustained release form. For most large mammals, the total daily dosageis from about 1.0 milligrams to about 1000 milligrams, or from about 1milligrams to about 50 milligrams. In the case of a 70 kg adult human,the total daily dose will generally be from about 7 milligrams to about350 milligrams. This dosage regimen may be adjusted to provide theoptimal therapeutic response.

It will be understood, however, that the specific dose level andfrequency of dosage for any particular patient may be varied and willdepend upon a variety of factors including the activity of the specificcompound employed, the metabolic stability and length of action of thatcompound, the age, body weight, general health, sex, diet, mode and timeof administration, rate of excretion, drug combination, the severity ofthe particular condition, and the host undergoing therapy.

Several methods for preparing the compounds of this invention areillustrated in the following Schemes and Examples. Starting materialsare made according to procedures known in the art or as illustratedherein.

The compounds of the present invention can be prepared readily accordingto the following Schemes and specific examples, or modificationsthereof, using readily available starting materials, reagents andconventional synthesis procedures. In these reactions, it is alsopossible to make use of variants which are themselves known to those ofordinary skill in this art but are not mentioned in greater detail. Thegeneral procedures for making the compounds claimed in this inventioncan be readily understood and appreciated by one skilled in the art fromviewing the following Schemes.

The synthesis of intermediates and final compounds may be conducted asdescribed in Schemes 1-16.

Reaction Schemes

The preparation of final compounds proceeds through intermediates suchas those of Formula III and Formula IV, and representative syntheses aredescribed herein.

In general, intermediates of the Formulae III and IV can be coupledthrough a urea linkage as shown in Scheme 1. Amine intermediate 1 can beconverted to a reactive carbamate, for example p-nitrophenylcarbamate 2,which is subsequently reacted with an amine like that of intermediate 3to produce urea 4. Other activated intermediates known to those skilledin the art can be used to prepare compounds like 4. For example, amine 1can be directly acylated with the appropriate carbamoyl chloride.

The synthesis of compounds represented by Intermediate IV can beaccomplished by procedures similar to those described in Henning et al.,J. Med. Chem., 1987, 30, 814-819; Carpino et al., WO 96/35713; Brown etal., J. Chem. Soc. 1957, 682-686; Barlin et al., Aust. J. Chem. 1982, 35(11), 2299-2306; and references cited therein.

Additionally, the synthesis of compounds represented by Intermediate IVcan be accomplished according to Schemes 2-6. For example, a diaminoheterocycle, such as 2,3-diaminopyridine 5, can be reductively alkylatedwith ketones such as 6 to give the monalkylated product 7 (Scheme 2).Ring closure with carbonyldiimidazole furnishes imidazolone 8. Finaldeprotection under standard conditions gives the intermediate 9.

Alternatively, as described in Scheme 3, a suitably protected4-ketopiperidine like 10 can be reductively alkylated with theappropriate α-amino ester, for example by allylglycine methyl ester (11,R⁶═H), which then would furnish 12. Treatment with trimethylsilylisocyanate yields hydantoin 13. Oxidative cleavage of the terminaldouble bond can be accomplished under standard conditions to affordaldehyde 14, which can be cyclized in the presence of hydrazine in warmacetic acid to deliver 15. Removal of the protecting group givescompounds like 16.

In Scheme 4, a suitably protected 4-aminopiperidine 17 can be arylatedby a SNAr reaction, for example using methyl2-bromopyrazine-3-carboxylate. The resulting product 18 can be convertedto an acyl azide via acyl hydrazide 19. Thermal rearrangement of theacyl azide (Curtius rearrangement) can occur with concomitant ringclosure to produce 20. Final deprotection under standard conditionsgives the desired heterocycles 21.

Additional heterocycles can be synthesized in a similar manner. Forexample, a heterocycle carboxaldehyde, such as 22 (J. Med. Chem. 1998,31, 2136-45) in Scheme 5, can be reductively aminated with amines suchas 23 to give the monoalkylated product 24. Deprotection with acid andring closure with carbonyldiimidazole furnishespyridodihydropyrimidinone 26. Final deprotection under standard basicconditions gives the product 27.

A similar synthetic strategy can be used to construct the relatedpyridodihydropyrimidinone of formula 29 starting from the commerciallyavailable aldehyde 28.

Alternatively, addition of a suitably protected amine, such as 31, tothe commercially available chloropyridine 30, followed by nitrilereduction affords the diamine 33 (Scheme 6). This diamino heterocyclecan be reductively alkylated with ketones such as 6 to give themonoalkylated product 34. Ring closure with carbonyldiimidazolefurnishes pyridodihydropyrimidinone 35. Final deprotection withtrifluoroacetic acid gives the product 36.

A similar synthetic strategy can be used to construct the relatedpyridodihydropyrimidinone of formula 38 starting from the known nitrile37.

Caprolactams can be assembled following an olefin metathesis strategy asoutlined in Scheme 7. 2,4-Dimethoxybenzylamine hydrochloride isalkylated with 2,3-dibromopropene under mild basic conditions to giveamine 39. (2R)-2-{[(benzyloxy)carbonyl]amino}pent-4-enoic acid 40,prepared in one step from commercially available D-allyl glycineaccording to known procedures (J. Chem. Soc., 1962, 3963-3968), can becoupled to amine 30 under a variety of conditions to give amide 41. Avariety of transition metal catalyzed cross couplings can be performedon the vinyl bromide, for example palladium-mediated arylations withphenylboronic acid and sodium carbonate, yielding styrene derivative 42.Ring-closing metathesis occurs in the presence of the Grubbs secondgeneration ruthenium catalyst in dichloromethane with mild heating toafford lactam 43. Removal of the dimethoxybenzyl group and hydrogenationwith in situ protection of the primary amine gives the correspondingsaturated lactam 45. After selective alkylation of the amide nitrogenwith various electrophiles such as alkyl bromides, deprotection underacidic conditions yields compounds of the general formula 47.

Alternatively, a C6-aryl group can be introduced as outlined in Scheme8. Addition of nitromethane to the known glutamic acid derived aldehyde48 (Tetrahedron Asymmetry, 1998, 3381-94), followed by in situelimination affords nitro olefin 49. Addition of the aryl group via aboronic acid derivative, or similar equivalent, can be accomplished in astereoselective manner through chiral ligand-Rh catalysis. Concomitantnitro reduction and benzyl ester hydrogenolysis affords the amino acid51. Ring closure under standard conditions, followed by removal of asingle tert-butoxycarbonyl group furnishes the lactam 45. Intermediatessuch as 51 can be further processed as in Scheme 9.

Alternatively, amino acid 51 can be alkylated, either reductively or viaan S_(N)2 displacement, to afford intermediates such as 53 (Scheme 9).Ring closure under standard conditions, followed by protecting groupremoval furnishes the lactam 55.

Variation at the 6-position of the caprolactams can be introduced byemploying a similar strategy (Scheme 10). Ring-closing metathesis can beperformed directly on vinyl bromide 41 using the Grubbs secondgeneration ruthenium catalyst to give cyclic vinyl bromide 56. Removalof the dimethoxybenzyl group and palladium-mediated cross coupling, inthis case with a boronic acid, furnishes compounds of the generalformula 58. The transformation of 57 to 58 is not limited to boronicacid derivatives. After standard hydrogenation, the amide nitrogen canbe selectively alkylated with various electrophiles, for example alkylbromides, using sodium hydride as base. Deprotection yields lactams ofthe general formula 61.

Alternatively, addition of a Grignard or similar reagent, to the nitroolefin 49, followed by nitro reduction and benzyl ester hydrogenolysisaffords various amino acids such as 63 (Scheme 11). Ring closure withEDC furnishes caprolactam 64. Final deprotection with trifluoroaceticacid gives the product 65.

The C7-position of the caprolactam can be varied as outlined in Scheme12. Addition of the nitroalkane to an aldehydre R²CHO, affords analcohol such as 66. Concomitant nitro reduction and benzyl esterhydrogenolysis affords the amino acid 67. Ring closure under standardconditions, followed by removal of the tert-butoxycarbonyl groupsfurnishes the lactam 69.

The oxazepanones can be prepared according to Scheme 13. (S)-(−)-Styreneoxide (or substituted derivatives) 70 can be opened by reaction withvarious primary amines in isopropanol solvent to afford thecorresponding amino alcohols 71. Selective N-protection followed byboron trifluoride etherate catalized aziridine opening of 73 (preparedaccording to known procedures: J. Chem. Soc., Perkins Trans. 1, 1994, 7,807-816) provides ether 74. Hydrolysis of the methyl ester, selectiveamine deprotection, and amide bond formation with diphenylphosphorylazide gives 76, which after standard hydrogenation conditions yieldsamine 77.

The 3-acetyl caprolactam derivatives can be prepared as outlined inScheme 14. Lactam 78 (prepared according to known procedures: J. Med.Chem., 1988, 31, 422-428) can be alkylated selectively at the amidenitrogen with a variety of electrophiles, such as alkyl bromides, usingsodium hydride as base. C-alkylation is achieved by generation of theenolate with lithium diisopropylamide followed by quenching withtert-butyl bromoacetate, giving ester 79. Deprotection of the carboxylgroup is accomplished with trifluoroacetic acid. Coupling of theresultant carboxylic acid with amine 9 under standard conditions affords3-acetyl lactams of the general formula 82.

Piperidinones are prepared as outlined in Scheme 15. Commerciallyavailable hydroxypyridine 89 can be selectively N-alkylated usingvarious electrophiles with cesium carbonate. Palladium-mediated crosscoupling with different aryl, heteroaryl, and alkyl groups affords thesubstituted pyridinones. Platinum catalyzed hydrogenation at 56 psiresults in both reduction of the olefins and the nitro group, givingdiastereomeric mixtures of the primary amine 92. Urea formation understandard conditions with the appropriate amine (eg, 9) yields the finaltargets 93.

Diazepinone derivatives can be prepared as shown in Scheme 16. Followingamine protection of the commercially available diazepinone 94,alkylation of various electrophiles with sodium hydride givessubstituted amides 96. Removal of the Cbz group and reductive aminationof various aldehydes or alkylation of different halides affords thedisubstituted diazepinones, such as 98, and final deprotection of theprimary amine with trifluoroacetic acid yields the urea couplingprecursor 99.

In some cases the final product may be further modified, for example, bymanipulation of substituents. These manipulations may include, but arenot limited to, reduction, oxidation, alkylation, acylation, andhydrolysis reactions which are commonly known to those skilled in theart. Moreover, in some cases the order of carrying out the foregoingreaction schemes may be varied to facilitate the reaction or to avoidunwanted reaction products.

INTERMEDIATES AND EXAMPLES

The following examples are provided so that the invention might be morefully understood. These examples are illustrative only and should not beconstrued as limiting the invention in any way.

2-Oxo-1-(4-piperidinyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridinedihydrochloride

Step A. 2-Amino-3-[(1-t-butoxycarbonylpiperidin-4-yl)amino)pyridine

Sodium triacetoxyborohydride (14.5 g, 68.7 mmol) was added to a solutionof 2,3-diaminopyridine (5.00 g, 45.8 mmol) andN-(t-butoxycarbonyl)-4-piperidone (9.58 g, 48.1 mmol) in dichloroethane(75 mL) at room temperature. After 5 h, additional sodiumtriacetoxyborohydride was added (1.8 g) and again after another 2.5 h.The reaction was stirred overnight, and quenched with 5% aqueous sodiumhydroxide. This was extracted with methylene chloride, and washed with5% aqueous sodium hydroxide, water and saturated sodium chloridesolution. After drying over sodium sulfate, the solution was filteredand evaporated to give the crude product. This was purified bychromatorgraphy (silica gel, 3 to 5% methanol in methylene chloridegradient elution), which gave the title compound (4.44 g). MS 293 (M+1)¹H NMR (500 MHz, CD₃OD) δ 7.32 (dd, J=1, 5 Hz, 1H), 6.85 (dd, J=1, 8 Hz,1H), 6.59 (dd, J=5, 8 Hz, 1H), 4.04 (d, J=13 Hz, 2H), 3.46 (m, 1H), 2.98(br s, 2H), 2.01 (dd, J=2, 12 Hz, 2H), 1.46 (s, 9H), 1.37 (qd, J=4, 12Hz, 2H).

Step B.2-Oxo-1-(1-t-butoxycarbonylpiperidin-4-yl)-2,3-dihydro-1H-imidazo[4,5-b]pyridine

Carbonyldiimidazole (0.70 g, 4.33 mmol) was added to a solution of2-amino-3-[(1-t-butoxycarbonylpiperidin-4-yl)amino]pyridine (1.15 g,3.93 mmol) in acetonitrile (150 mL) at room temperature. After severalhours, an additional amount of carbonyldiimidazole was added (0.81 g),and the reaction stirred overnight. The acetonitrile was evaporated invacuo, the residue partitioned between water and chloroform, and theorganic phase washed with saturated brine and dried over magnesiumsulfate. The crude product was purified by chromatography (silica gel,1.2 to 2.5% methanol in methylene chloride gradient elution), which gavethe title compound (1.09 g). ¹H NMR (500 MHz, CDCl₃) δ 9.39 (br s, 1H),8.04 (dd, J=1, 5 Hz, 1H), 7.33 (dd, J=1, 8 Hz, 1H), 6.99 (dd, J=5, 8 Hz,1H), 4.50 (m, 1H), 4.32 (br s, 2H), 2.86 (br s, 2H), 2.20 (m, 2H), 1.86(d, J=12 Hz, 2H), 1.50 (s, 9H).

Step C. 2-Oxo-1-(4-piperidinyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridinedihydrochloride

2-Oxo-1-(1-t-butoxycarbonylpiperidin-4-yl)-2,3-dihydro-1H-imidazo[4,5-b]pyridine(1.03 g, 3.23 mmol) was dissolved in methanol (25 mL) and a solution of2N hydrochloric acid in ether (8 mL) was added at room temperature.After 2 h, the volatiles were removed in vacuo, to give the titlecompound (0.92 g). MS 219 (M+1). ¹H NMR (500 MHz, CD₃OD) δ 8.01 (dd,J=1, 6 Hz, 1H), 7.83 (d, J=8 Hz, 1H), 7.28 (dd, J=6, 8 Hz, 1H), 4.60 (m,1H), 3.59 (d, J=12 Hz, 2H), 3.21 (t, J=12 Hz, 2H), 2.70 (dq, J=4, 13 Hz,2H), 2.12 (d, J=13 Hz, 2H).

4-(2-Oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carbonylchloride

Phosgene (20% wt. in toluene; 1.8 mL, 3.43 mmol) was added to asuspension of2-oxo-1-piperidinium-4-yl-2,3-dihydro-1H-imidazo[4,5-b]pyridin-4-iumdichloride (100 mg, 0.343 mmol) and 2,6-lutidine (0.50 mL, 4.293 mmol)in dichloromethane (5 mL) at 0° C. After 2 h, the solution was added tosaturated aqueous sodium bicarbonate and extracted with ethyl acetate.The organic layer was washed with water (2×), saturated brine, driedover magnesium sulfate, filtered and concentrated. Dichloromethane (10mL) was added, and the mixture was filtered to give the title compoundas a solid (48 mg). MS 281 (M+1). ¹H NMR (500 MHz, (CD₃)₂SO) δ 11.58 (s,1H), 7.90 (d, J=5.1 Hz, 1H), 7.67 (d, J=7.6 Hz, 1H), 7.01-6.99 (m, 1H),4.52-4.46 (m, 1H), 4.31-4.23 (m, 2H), 3.38-3.33 (m, 1H), 3.19-3.14 (m,1H), 2.32-2.24 (m, 2H), 1.84-1.81 (m, 2H).

1-Piperidin-4-yl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one 4-oxide

Step A. tert-Butyl4-(4-oxido-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate

2-Oxo-1-(1-t-butoxycarbonylpiperidin-4-yl)-2,3-dihydro-1H-imidazo[4,5-b]pyridine(63 mg, 0.198 mmol) was dissolved in 1,2-dichloroethane (10 mL) and3-chloroperoxybenzoic acid (137 mg, 0.792 mmol) was added at 0° C. Thereaction was warmed to room temperature and stirred for 4 h. Thereaction was quenched with saturated aqueous sodium bicarbonate andsodium thiosulfate, extracted with methylene chloride (3×), dried oversodium sulfate, filtered and evaporated to give the title compound (45mg). MS 335.1 (M+1).

Step B. 1-Piperidin-4-yl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one4-oxide

tert-Butyl4-(4-oxido-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate(45 mg, 0.135 mmol) was dissolved in dichloromethane (10 mL) andtrifluoroacetic acid (5 mL) was added at room temperature. After 3 h,the volatiles were removed in vacuo to give the title compound as itsTFA salt. MS 235.2 (M+1).

2-Oxo-3-(4-piperidinyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridinedihydrobromide

Step A. Ethyl 4-(pyridin-4-ylamino)piperidine-1-carboxylate

A solution of ethyl 4-aminopiperidine-1-carboxylate (2.20 g, 12.7 mmol),4-bromopyridine (3.47 g, 17.8 mmol), sodium t-butoxide (4.54 g, 47.2mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.398 g, 0.639 mmol)and palladium acetate (0.143 g, 0.639 mmol) in toluene (40 mL) washeated at 60° C. overnight. The reaction was cooled and partitionedbetween ethyl acetate and water. The aqueous layer was washed 3 timeswith methylene chloride, and the combined organic layers dried oversodium sulfate. The crude product was purified by chromatography (silicagel, 0 to 10% {5% ammonium hydroxide in methanol} in methylene chloridegradient elution), which gave the title compound (1.3 g, 41% yield).

Step B. Ethyl 4-[(3-nitropyrin-4-yl)amino]piperidine-1-carboxylate

A solution of ethyl 4-(pyridin-4-ylamino)piperidine-1-carboxylate (1.30g, 5.21 mmol) in 90% sulfuiric acid (17 mL) was cooled to 0° C. To thiswas added 70% nitric acid (1.2 mL) in 90% sulfuric acid (8 mL). Thereaction was stirred at 0° C. for 1.5 h, then poured into ice water (150mL). Solid sodium carbonate was added to render the solution basic. Thismixture was extracted four times with methylene chloride, dried,filtered and concentrated. The crude product was purified bychromatography (silica gel, 0 to 10% {5% ammonium hydroxide in methanol}in methylene chloride gradient elution), which gave the title compound(1.09 g, 71% yield).

Step C. Ethyl 4-[(3-aminopyrin-4-yl)amino]piperidine-1-carboxylate

Ethyl 4-[(3-nitropyrin-4-yl)amino]piperidine-1-carboxylate (1.09 g, 3.70mmol) in ethanol was hydrogenated (1 atm hydrogen) over 30% palladium oncarbon (300 mg) for 4 h. The reaction was filtered through celite andconcentrated in vacuo, to give the title compound (0.98 g, 100%).

Step D. Ethyl4-[(2-oxo-2,3-dihydro-1H-imidazol[4,5-c]pyridin-1-yl)piperidine-1-carboxylate

A solution of ethyl 4-[(3-aminopyrin-4-yl)amino]piperidine-1-carboxylate(0.98 g, 3.70 mmol) and carbonyldiimidazole (1.80 g, 11.1 mmol) intetrahydrofuran (40 mL) was refluxed until starting material wasconsumed. The solvent was removed in vacuo and the crude productpurified by chromatography (silica gel, 0 to 10% {5% ammonium hydroxidein methanol} in methylene chloride gradient elution). Fractionscontaining product were dissolved in methylene chloride and washed withsaturated sodium carbonate to remove co-eluting imidazole. The organicphase was dried over sodium sulfate, filtered and concentrated to givethe title compound (0.360 g, 33% yield).

Step E. 2-Oxo-1-(4-piperidinyl)-2,3-dihydro-1H-imidazol[4,5-c]pyridinedihydrobromide

A solution of ethyl4-[(2-oxo-2,3-dihydro-1H-imidazol[4,5-c]pyridin-1-yl)piperidine-1-carboxylate(0.120 g, 0.413 mmol) in 30% hydrogen bromide/acetic acid (1 mL) washeated at 70° C. overnight. The reaction was cooled and concentrated invacuo. The resulting solid was triturated with methylene chloride anddried, giving the title compound (0.123 g, 78% yield). ¹H NMR (500 MHz,CD₃OD) δ 8.48 (d, J=6 Hz, 1H), 8.46 (s, 1H), 7.94 (d, J=6 Hz, 1H), 4.80(m, 1H), 3.60 (d, J=10 Hz, 2H), 3.30 (m, partially obscured by solventpeak), 2.81 (dq, J=4,12 Hz, 2H), 2.16 (d, J=12 Hz, 2H).

2-Oxo-3-(4-piperidinyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridine

Step A. 4-Amino-3-[(1-benzylpiperidin-4-yl)amino)pyridine

A mixture of 3,4-diaminopyridine (1.1 g, 10.1 mmol),1-benzyl-4-piperidone (3.2 g, 16.9 mmol) sodium triacetoxyborohydride(4.0 g, 18.9 mmol), and acetic acid (10.7 mL) in dichloroethane (10 mL)was stirred for about 6 days at room temperature. The reaction wasconcentrated to near dryness, and partitioned between chloroform (5×50mL) and 1N sodium hydroxide (50 mL). The organic phase was dried overmagnesium sulfate and concentrated to give the title compound (2.8 g).MS 283 (M+1).

Step B.2-Oxo-3-(1-benzylpiperidin-4-yl)-2,3-dihydro-1H-imidazo[4,5-c]pyridine

A solution of 4-amino-3-[(1-benzylpiperidin-4-yl)amino)pyridine (2.8 g,9.9 mmol) and carbonyldiimidazole (3.0 g, 18.5 mmol) in tetrahydrofuran(100 mL) was refluxed overnight. The reaction was cooled, concentratedand partitioned between chloroform (500 mL) and saturated sodiumcarbonate (100 mL). The organic phase was dried over magnesium sulfateand concentrated to give the title compound (2.8 g). MS 209 (M+1).

Step C. 2-Oxo-3-(4-piperidinyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridine

A solution of2-oxo-3-(1-benzylpiperidin-4-yl)-2,3-dihydro-1H-imidazo[4,5-c]pyridine(0.5 g, 1.6 mmol) in methanol (250 mL) was shaken with 20% Pd(OH)₂ undera hydrogen atmosphere for 48 h at room temperature. The reaction wasfiltered and concentrated to give the title compound as a white solid(0.3 g). MS 219 (M+1).

2-Oxo-1-(4-piperidinyl)-2,3-dihydro-1H-imidazo[4,5-b]pyrazine

Step A. Methyl 3-[(1-benzylpiperidin-4-yl)amino]pyrazine-2-carboxylate

A mixture of methyl 2-bromopyrazine-3-carboxylate (J. Med. Chem., 1969,12, 285) (2.2 g, 10.1 mmol) and 4-amino-1-benzylpiperidine (2.0 g, 10.5mmol) was refluxed in 2-propanol overnight. Thin layer chromatography(10% methanol in ethyl acetate) showed the reaction was complete. Thesolvent was evaporated, and the crude product dissolved in chloroform(100 mL), which was washed with saturated sodium carbonate solution (20mL), and dried over magnesium sulfate. The title compound was obtainedas a gum (3.8 g). MS 327 (M+1).

Step B. 3-[(1-Benzylpiperidin-4-yl)amino]pyrazine-2-carbohydrazide

A mixture of methyl3-[(1-benzylpiperidin-4-yl)amino]pyrazine-2-carboxylate (3.0 g, 9.2mmol) and hydrazine hydrate (6 mL) in ethanol (100 mL) was refluxed withstirring for 2 h. The reaction was cooled and concentrated to give thetitle compound (3.0 g). MS 327 (M+1).

Step C.2-Oxo-1-(1-benzylpiperidin-4-yl)-2,3-dihydro-1H-imidazo[4,5-b]pyrazine

3-[(1-Benzylpiperidin-4-yl)amino]pyrazine-2-carbohydrazide (3.0 g, 9.2mmol) was dissolved in 1N HCl (20 mL) and water (40 mL), and cooled to0° C. To this was added aqueous sodium nitrite (0.8 g, 11.6 mmol) inwater (5 mL). After 0.5 h sodium bicarbonate was added and the basicsolution extracted with chloroform (5×50 mL), which was dried overmagnesium sulfate. The crude acyl azide was dissolved in methoxyethanol(20 mL) and heated at 180° C. for 3 h. The progress of the reaction wasmonitored by thin layer chromatography (10% methanol in chloroform). Thereaction was cooled and concentrated, and the crude product purified bypreparative thin layer chromatography (silica gel, 75:25tetrahydrofuran:hexane) to give the title compound (1.7 g). MS 310(M+1).

Step D. 2-Oxo-1-(4-piperidinyl)-2,3-dihydro-1H-imidazo[4,5-b]pyrazine

2-Oxo-1-(1-benzylpiperidin-4-yl)-2,3-dihydro-1H-imidazo[4,5-b]pyrazine(1.7 g, 5.5 mmol) was dissolved in methanol (100 mL) and hydrogenatedover 20% palladium on carbon (0.5 g) at 55 psi hydrogen overnight. Thecatalyst was filtered and solvent evaporated to give the title compound(1.5 g).

7-Piperidin-4-yl-7,9-dihydro-8H-purin-8-one hydrochloride

Step A. 4-Amino-5-[(1-t-butoxycarbonylpiperidin-4-yl)amino)pyrimidine

A mixture of 4,5-diaminopyrimidine (1.0 g, 9.1 mmol),N-(t-butoxycarbonyl)-4-piperidone (3.0 g, 15 mmol) and sodiumtriacetoxyborohydride (1.2 g, 5.6 mmol) in dichloroethane (60 mL) wasstirred at room temperature for 3 d. The reaction was partitionedbetween chloroform (200 mL) and 3N sodium hydroxide (30 mL). Afterdrying over magnesium sulfate, the organic phase was concentrated togive the title compound as a tan gum. MS 294 (M+1)

Step B. 7-(1-Benzalpiperidin-4-yl)-7,9-dihydro-8H-purin-8-one

The crude product from Step A,4-amino-5-[(l-t-butoxycarbonylpiperidin-4-yl)amino)pyrimidine, wasrefluxed with carbonyldiimidazole (3.0 g, 18 mmol) in tetrahydrofuran(250 mL) for 2 d, cooled and concentrated. The crude product wasdissolved in ethyl acetate (25-50 mL), which in four crops gave thetitle compound as a white crystalline solid (1.3 g). MS 320 (M+1)

Step C. 7-Piperidin-4-yl-7,9-dihydro-8H-purin-8-one hydrochloride

A mixture of 7-(1-benzylpiperidin-4-yl)-7,9-dihydro-8H-purin-8-one (1.2g, 3.7 mmol) in 4N hydrogen chloride in dioxane (50 mL), was stirredvigorously at room temperature for 3 h. The reaction was concentrated invacuo to give the title compound as a white solid. MS 220 (M+1)

5-Piperidin-4-yl-5,7-dihydro-6H-imidazo[4,5-c]pyridazin-6-one

Step A. Benzyl4-{[1-(methoxycarbonyl)but-3-en-1-yl]amino}piperidine-1-carboxylate

Sodium triacetoxyborohydride (11.2 g, 52.6 mmol) was added to a solutionof methyl 2-aminopent-4-enoate (3.4 g, 26.3 mmol), acetic acid (2.37 g,39.5 mmol) and benzyl 4-oxopiperidine-1-carboxylate (9.21 g, 39.5 mmol)in dichloroethane (60 mL) at room temperature. After 3 h, the reactionwas quenched with saturated aqueous sodium bicarbonate, extracted withmethylene chloride (3×), dried over sodium sulfate, filtered andevaporated to give the crude product. This was purified bychromatography (silica gel, 0 to 8% methanol in methylene chloridegradient elution), which gave the title compound (9.42 g). MS 347.2(M+1).

Step B. Benzyl4-(5-allyl-2,4-dioxoimidazolidin-1-yl)piperidine-1-carboxylate

Trimethylsilyl isocyanate (1.66 g, 14.4 mmol) was added to a solution ofbenzyl4-{[1-(methoxycarbonyl)but-3-en-1-yl]amino}piperidine-1-carboxylate(2.00 g, 5.77 mmol) and DMAP (71 mg, 0.57 mmol) in THF (30 mL) at roomtemperature. The reaction was heated at 50° C. for 48 h. The reactionwas quenched with saturated aqueous sodium bicarbonate, extracted withmethylene chloride (3×), dried over sodium sulfate, filtered andevaporated to give the crude product. The crude product was purified bychromatography (silica gel, 0 to 20% methanol in methylene chloridegradient elution), which gave the title compound (1.66 g). MS 358.2(M+1).

Step C. Benzyl4-(6-oxo-6,7-dihydro-5H-imidazo[4,5-c]pyridazin-5-yl)piperidine-1-carboxylate

Benzyl 4-(5-allyl-2,4-dioxoimidazolidin-1-yl)piperidine-1-carboxylate(0.480 g, 1.34 mmol) was dissolved in THF (5 mL), and osmium tetroxide(0.05 mL, 2.5% solution in t-butanol) was added followed by a solutionof sodium periodate (0.862 g, 4.03 mmol) in water (4 mL). After 24 h,the reaction was diluted with saturated aqueous Na₂SO₃ and NaHCO₃ andextracted with ethyl acetate (4×). The combined organic washes weredried over sodium sulfate, filtered and evaporated to give the crudealdehyde (0.352 g). To a portion of this material (0.250 g, 0.696 mmol)in acetic acid (10 mL) was added hydrazine (0.446 ML, 13.9 mmol). Thismixture was heated at 50° C. for 24 h, and then concentrated to dryness.Purification by reverse phase HPLC (C-18, 95% water/acetonitrile→5%water/acetonitrile with 0.1% trifluoroacetic acid) gave the product(0.032 g). MS 354.2 (M+1).

Step D. 5-Piperidin-4-yl-5,7-dihydro-6H-imidazo[4,5-c]pyridazin-6-one

A solution of benzyl4-(6-oxo-6,7-dihydro-5H-imidazo[4,5-c]pyridazin-5-yl)piperidine-1-carboxylate(35 mg, 0.099 mmol) and 10% Pd/C (50 mg) in EtOH (5 mL), washydrogenated under a balloon overnight. The reaction was filteredthrough Celite with more EtOH and concentrated to afford the titlecompound (26 mg). MS 220.2 (M+1).

5-Methoxy-2-oxo-1-(4-piperidinyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridinedihydrochloride

Step A. 2-Amino-6-chloro-3-nitropyridine

A solution of ammonium hydroxide (6.6 g, 0.124 mol) and sodium hydroxide(4.8 g, 0.120 mol) in water (45 mL) was added to2,6-dichloro-3-nitropyridine (12.0 g, 0.62 mol) in ethanol (240 mL). Thereaction was refluxed for 2 h, cooled to room temperature and filtered.The pale yellow solid was dried overnight to give the title compound. ¹HNMR (500 MHz, CDCl₃) δ 8.87 (d, J=9 Hz, 1H), 7.8 (br s, 1H), 6.73 (d,J=9 Hz, 1H), 5.9 (br s, 1H).

Step B. 2-Amino-6-methoxy-3-nitropyridine

Sodium metal (0.5 g, 21.7 mmol) was added portion wise to anhydrousmethanol mL) under argon. When the sodium was consumed,1-amino-6-chloro-3-nitropyridine (3.0 g, 17.2 mmol) and methanol (30 mL)were added, and the suspension refluxed for 2 h. The reaction was cooledto room temperature and stirred for 3 h. The yellow solid was filteredand air dried to give the title compound. MS 170 (M+1) ¹H NMR (500 MHz,CDCl₃) δ 8.29 (d, J=9 Hz, 1H), 7.8 (br s, 1H), 6.14 (d, J=9 Hz, 1H), 5.6(br s, 1H).

Step C. 2,3-Diamino-6-methoxypyridine

2-Amino-6-methoxy-3-nitropyridine (2.8 g, 16.5 mmol) was dissolved inwarm 1:1 methanol/ethanol (200 mL). The solution was cooled, purged withargon, and 10% palladium on carbon was added (0.45 g). Hydrogen wasintroduced (1 atm) and the reaction stirred until complete. The catalystwas filtered and the solvent evaporated from the filtrate to give thetitle compound. MS 140 (M+1) ¹H NMR (500 MHz, CDCl₃) δ 6.93 (d, J=8 Hz,1H), 6.04 (d, J=8 Hz, 1H), 4.15(br s, 2H), 3.80 (s, 3H), 3.0 (br s, 2H).

Step D.2-Amino-3-[(1-t-butoxycarbonylpiperidin-4-yl)amino)-6-methoxypyridine

Sodium triacetoxyborohydride (3.39 g, 16.0 mmol) was added to a solutionof 2,3-diamino-6-methoxypyridine (2.23 g, 16.0 mmol) andN-(t-butoxycarbonyl)-4-piperidone (7.66 g, 38.4 mmol) in dichloroethane(50 mL) at room temperature. The reaction was quenched with water (50mL) and stirred overnight, then extracted with chloroform and washedwith 5% aqueous sodium hydroxide, water and saturated sodium chloridesolution. After drying over sodium sulfate, the solution was filteredand evaporated to give the crude product. This was purified bychromatography, where the more polar product was isolated (silica gel,50% ethyl acetate hexane, R_(f)=0.36), to give the title compound. MS323 (M+1). ¹H NMR (500 MHz, CDCl₃) δ 7.99 (d, J=8 Hz, 1H), 6.05 (d, J=8Hz, 1H), 4.45 (br s), 4.03 (br s), 3.83 (s, 3H), 3.15 (m, 1H), 2.86 (m,2H), 1.91 (d, J=12 Hz, 2H), 1.5 (br s, 11H), 1.26 (br s, 2H).

Step E.5-Methoxy-2-oxo-1-(1-t-butoxycarbonylpiperidin-4-yl)-2,3-dihydro-1H-imidazo[4,5-b]pyridine

Carbonyldiimidazole (1.6 g, 9.8 mmol) was added to a solution of2-amino-3-[(1-t-butoxycarbonylpiperidin-4-yl)amino]-6-methoxypyridine(1.29 g, 4.00 mmol) in acetonitrile (100 mL) at room temperature. Thereaction was stirred until all the starting material was consumed.Methanol was added to the reaction and the solution stirred for severalhours, then the solvent was evaporated in vacuo. The residue wasdissolved in ethyl acetate, washed with water and saturated brine, andthen dried over magnesium sulfate. The crude product was purified bychromatography (silica gel, 2.5% to 5% methanol in methylene chloridegradient elution), which gave the title compound. MS 349 (M+1) ¹H NMR(500 MHz, CDCl₃) δ 8.50 (br s, 1H), 7.29 (d, J=8 Hz, 1H), 6.43 (d, J=8Hz, 1H), 4.46 (m, 1H), 4.31 (br s, 2H), 3.90 (s, 3H), 2.85 (br s, 2H),2.13 (m, 2H), 1.85 (d, J=12 Hz, 2H), 1.50 (s, 9H).

Step F.5-Methoxy-2-oxo-1-(4-piperidinyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridine

5-Methoxy-2-oxo-1-(1-t-butoxycarbonylpiperidin-4-yl)-2,3-dihydro-1H-imidazo[4,5-b]pyridine(100 mg, 0.287 mmol) was dissolved in methanol (2.5 mL) and a solutionof 2N hydrochloric acid in ether (3 mL) was added at room temperature.After 2 h, the volatiles were removed in vacuo, to give the titlecompound (61 mg). MS 249.1 (M+1).

4-Fluoro-2-oxo-1-(4-piperidinyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridine

Step A. N-(5-Fluoropyridin-2-yl)-2,2-dimethylpropanamide

To a 0° C. solution of 2-amino-5-fluoropyridine (1.00 g, 8.92 mmol) andtriethylamine (1.35 g, 13.4 mmol) in dichloromethane (30 mL) was addedtrimethylacetyl chloride (1.29 g, 10.7 mmol) and DMAP (0.11 g, 0.89mmol). The solution was allowed to warm to room temperature. After 4 h,saturated aqueous NaHCO₃ was added, the layers separated and the aqueousphase backwashed with DCM. The combined organics were dried overmagnesium sulfate, filtered and concentrated and the residue purified bysilica gel chromatography (5%→40% EtOAc/hexanes) to give the titlecompound (1.34 g). MS 197.3 (M+1).

Step B. N-(3-Azido-5-fluoropyridin-2-yl)-2,2-dimethylpropanamide

To a −78° C. solution ofN-(5-fluoropyridin-2-yl)-2,2-dimethylpropanamide (1.34 g, 6.83 mmol) intetrahydrofuran (25 mL) was added tert-butyllithium (1.31 mL of a 1.7 Msolution, 20.5 mmol) drop wise. After 3 h at −78° C.,4-dodecylbenzenesulfonyl azide (3.60 g, 10.2 mmol) was added at thereaction was allowed to warm to room temperature. After 1 h, saturatedaqueous NH₄Cl was added, and the tetrahydrofuran was removed via rotaryevaporator. Dichloromethane was added, the layers separated and theaqueous phase backwashed with DCM. The combined organics were dried overmagnesium sulfate, filtered and concentrated and the residue purified bytwo successive silica gel chromatographies (10%→80% EtOAc/hexanes, then5%→42% EtOAc/hexanes) to give the title compound (0.275 g). MS 234.0(M+1).

Step C. 3-Azido-5-fluoropyridin-2-amine

N-(3-Azido-5-fluoropyridin-2-yl)-2,2-dimethylpropanamide (275 mg, 1.16mmol) in 3 N HCl (5 mL) was heated to 100° C. After 2 h, the volatileswere removed in vacuo, to give the title compound as its HCl salt (180mg). MS 154.2 (M+1).

Step D. 5-Fluoropyridine-2,3-diamine

The HCl salt of 3-azido-5-fluoropyridin-2-amine (1.90 g, 10.0 mmol) wasdissolved in tetrahydrofuran (100 mL) and treated with MP-Carbonate(Argonaut, 11.5 g). After 1 h, the mixture was filtered, rinsed withmore tetrahydrofuran, and concentrated. This residue was dissolved inethanol (50 mL), purged with argon, and 10% palladium on carbon wasadded (0.15 g). Hydrogen was introduced (1 atm) and the reaction stirreduntil complete. The catalyst was filtered and the solvent evaporatedfrom the filtrate to give the title compound (1.18 g). MS 128.0 (M+1)

Step E. tert-Butyl4-[(2-amino-5-fluoropyridin-3-yl)amino]piperidine-1-carboxylate

Sodium triacetoxyborohydride (2.95 g, 13.9 mmol) was added to a solutionof 5-fluoropyridine-2,3-diamine (1.18 g, 9.28 mmol), acetic acid (0.56g, 9.28 mmol) and I-(t-butoxycarbonyl)-4-piperidone (1.85 g, 9.28 mmol)in 1,2-dichloroethane (20 mL) at room temperature. After 1 h, thereaction was quenched with water (20 mL) and extracted withdichloromethane. After drying over sodium sulfate, the solution wasfiltered and evaporated to give the crude product. This was purified bychromatography, (silica gel, 5%→15% MeOH/DCM; then C-18, 95%water/acetonitrile→5% water/acetonitrile with 0.1% trifluoroacetic acid)to give the title compound (0.73 g). MS 311.2 (M+1).

Step F. tert-Butyl4-(6-fluoro-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate

Carbonyldiimidazole (1.53 g, 9.41 mmol) was added to a solution oftert-butyl4-[(2-amino-5-fluoropyridin-3-yl)amino]piperidine-1-carboxylate (0.73 g,2.35 mmol) in acetonitrile (10 mL) at room temperature. The reaction wasstirred until all the starting material was consumed (approximately 2 h)and then the solvent was evaporated in vacuo. The residue was dilutedwith water, extracted with dichloromethane (3×), dried over magnesiumsulfate and then concentrated. The crude product was purified bychromatography (silica gel, 1% to 10% methanol in methylene chloridegradient elution), which gave the title compound (0.309 g). MS 337.2(M+1)

Step G.4-Fluoro-2-oxo-1-(4-piperidinyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridine

tert-Butyl4-(6-fluoro-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate(340 mg, 1.01 mmol) was dissolved in dichloromethane (5 mL) andtrifluoroacetic acid (5 mL) was added. After 2 h, the reation wasconcentrated, diluted with dichlormethane (5 mL) and a solution of 1Nhydrochloric acid in 1,4-dioxane (2 mL) was added at room temperature.Concentration afforded the title compound (302 mg). MS 237.2 (M+1) ¹HNMR (500 MHz, CDODl₃) δ 7.92 (br s, 1H), 7.70 (dd, 1H), 4.60 (m, 1H),3.60 (s, 2H), 3.25 (dd, 2H), 2.70 (m, 2H), 2.10 (d, 2H).

3-Piperidin-4-yl-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

Step A. Ethyl4-[({4-[(tert-butoxycarbonyl)amino]pyridin-3-yl}methyl)amino]piperidine-1-carboxylate

Sodium triacetoxyborohydride (1.70 g, 8.03 mmol) and acetic acid (0.29,4.82 mmol) were added to a solution of N-Boc-4-amino-3-pyridinecarboxaldehyde (0.36 g, 1.61 mmol) and ethyl4-aminopiperidine-1-carboxylate (0.33 g, 1.93 mmol) in dichloroethane (5mL) at room temperature. The reaction was stirred overnight, andquenched with saturated aqueous sodium bicarbonate. This was separated,extracted with ethyl acetate and the combined organics were dried oversodium sulfate. The solution was filtered and evaporated to give thecrude product. This was purified by chromatography (silica gel, 0 to 12%methanol in methylene chloride gradient elution), which gave the titlecompound (0.24 g). MS 379.2.

Step B. Ethyl 4-(2-oxo-1,4-dihydropyrido[4,3-d]pyrimidin-3(2H)-yl)piperidine-1-carboxylate

Trifluoroacetic acid (0.50 mL) was a add to a solution of the materialfrom Step A (0.24 g, 0.63 mmol) in dichloromethane (5 mL). Afterstirring overnight, another 0.5 mL of trifluoroacetic acid was added.After an additional 2 h, the reaction was concentrated. This materialwas dissolved in acetonitrile (5 mL) and carbonyldiimidazole (0.31 g,1.89 mmol) was added at room temperature. After 2 h, the acetonitrilewas evaporated in vacuo, the residue partitioned between 1N NaOH anddichloromethane, and the organic phase dried over magnesium sulfate. Thecrude product was purified by chromatography (silica gel, 10 to 15%methanol in methylene chloride gradient elution), which gave the titlecompound (0.089 g). MS 305.3.

Step C. 3-Piperidin-4-yl-3,4-dihydropyrido[4,3-d]pyirimidin-2(1H)-one

Ethyl 4-(2-oxo-1,4-dihydropyrido[4,3-d]pyrimidin-3(2H)-yl)piperidine-1-carboxylate (0.089 g, 0.29 mmol) was diluted in 1NNaOH (5 mL) and heated to reflux. After 4 h, the reaction wasconcentrated in vacuo, the residue was diluted with MeOH:DCM, filteredand concentrated. The crude material was purified by reverse phase HPLC(C-18, 5% to 95% 0.1% trifluoroacetic acid/acetonitrile in 0.1% aqueoustrifluoroacetic acid gradient elution) to give TFA salt of the titlecompound (0.12 g). MS 233.3 (M+1).

3-Piperidin-4-yl-3,4-dihydropyrido[3,4-d]pyrimidin-2(1H)-one

Step A. Ethyl4-[(1,3-[(tert-butoxycarbonyl)amino]pyridin-4-yl]methyl)amino]piperidine-1-carboxylate

Sodium triacetoxyborohydride (0.57 g, 2.70 mmol) and acetic acid (0.41,6.75 mmol) were added to a solution of N-Boc-3-amino-4-pyridinecarboxaldehyde (0.50 g, 2.25 mmol) and ethyl4-aminopiperidine-1-carboxylate (0.47 g, 2.70 mmol) in dichloroethane (5mL) at room temperature. The reaction was stirred overnight, andquenched with saturated aqueous sodium bicarbonate. This was separated,extracted with ethyl acetate and the combined organics were dried oversodium sulfate. The solution was filtered and evaporated to give thecrude product. This was purified by chromatography (silica gel, 1 to 12%methanol in methylene chloride gradient elution), which gave the titlecompound (0.47 g). MS 379.3.

Step B. Ethyl4-(2-oxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)piperidine-1-carboxylate

Trifluoroacetic acid (1.43 g) was added to a solution of the materialfrom Step A (0.47 g, 1.24 mmol) in dichloromethane (10 mL). Afterstirring overnight, the reaction was concentrated. This material wasdissolved in acetonitrile (5 mL) and carbonyldiimidazole (0.62 g, 3.73mmol) was added at room temperature. After 2 d, the acetonitrile wasevaporated in vacuo, the residue partitioned between 1N NaOH anddichloromethane, and the organic phase dried over magnesium sulfate. Thecrude product was purified by chromatography (silica gel, 1 to 20%methanol in methylene chloride gradient elution), which gave the titlecompound (0.15 g). MS 305.2.

Step C. 3-Piperidin-4-yl-3,4-dihydropyrido[3,4-d]pyrimidin-2(1H)-one

Ethyl4-(2-oxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)piperidine-1-carboxylate(0.15 g, 0.48 mmol) was diluted in 1N NaOH (10 mL) and heated to reflux.After 5 h, the reaction was concentrated in vacuo, the residue wasdiluted with MeOH:DCM, filtered and concentrated. The crude material waspurified by reverse phase HPLC (C-18, 5% to 95% 0.1% trifluoroaceticacid/acetonitrile in 0.1% aqueous trifluoroacetic acid gradient elution)to give TFA salt of the title compound (0.17 g). MS 233.3 (M+1).

3-Piperidin-4-yl-3,4-dihydropyrido[2,3-d]pyrimidin-2(1H)-one

Step A. 2-[(2,4-Dimethoxybenzyl)amino]nicotinonitrile

2,4-Dimethoxybenzylamine (2.90 g, 17.3 mmol) and triethylamine (1.75 g,17.3 mmol) were added sequentially to a solution of2-chloronicotinonitrile (2.0 g, 14.4 mmol) in N,N-dimethylacetamide (29mL). The reaction was heated at 80° C. for 4 h, quenched with water andextracted with diethyl ether (3×). The combined organic extracts werewashed water, saturated brine, dried over magnesium sulfate andconcentrated. The crude product was purified by flash chromatography(silica gel, 0-5% ethyl acetate (with 0.1 triethylamine) indichloromethane gradient elution) to produce the title compound (2.80g). MS 270.3 (M+1).

Step B. 3-(Aminomethyl)-N-(2,4-dimethoxybenzyl)pyridin-2-amine

Lithium aluminum hydride (1.0 M in THF, 11.4 mL, 11.4 mmol) was addedslowly to a solution of 2-[(2,4-dimethoxybenzyl)amino]nicotinonitrile(2.80 g, 10.4 mmol) in tetrahydrofuran (35 mL) at 0° C. The reaction wasallowed to warm to room temperature and stir for 4 h. The reaction wascarefully quenched with a saturated aqueous solution of sodium sulfate,filtered with copious dichloromethane and concentrated to produce thetitle compound (2.92 g). MS 274.3 (M+1).

Step C. tert-Butyl4-[({2-[(2,4-dimethoxybenzal)amino]pyridin-3-yl}methyl)amino]piperidine-1-carboxylate

Sodium triacetoxyborohydride (0.78 g, 3.66 mmol) and acetic acid (0.22g, 3.66 mmol) were added to a solution of a portion of the material formStep B (1.00 g, <3.66 mmol) and N-(t-butoxycarbonyl)-4-piperidone (0.73g, 3.66 mmol) in dichloroethane (20 mL) at room temperature. After 3 h,the reaction was washed with saturated aqueous sodium bicarbonate, driedover sodium sulfate, the solution was filtered and evaporated to givethe product (1.83 g). MS 457.3 (M+1).

Step D. tert-Butyl4-[1-(2,4-dimethoxybenzyl)-2-oxo-1,4-dihydropyrido[2,3-d]pyrimidin-3(2H)-yl]piperidine-1-carboxylate

Carbonyldiimidazole (0.65 g, 4.0 mmol) was added to a solution of thematerial from Step C in dimethylformamide (20 mL) and the reaction washeated to 150° C. After 1 d, further carbonyldiimidazole (0.65 g, 4.0mmol) was added and the reaction heated for an additional 3 h. Thereaction was diluted with water and extracted with dichloromethane, andthe organic phase dried over sodium sulfate. The crude product waspurified by chromatography (silica gel, 20 to 80% ethyl acetate inmethylene chloride gradient elution), which gave the title compound(0.35 g). MS 483.3 (M+1).

Step E. 3-Piperidin-4-yl-3,4-dihydropyido[2,3-d]pyrimidin-2(1H)-one

tert-Butyl4-[1-(2,4-dimethoxybenzyl)-2-oxo-1,4-dihydropyrido[2,3-d]pyrimidin-3(2H)-yl]piperidine-1-carboxylate(0.21 g, 0.43 mmol) was dissolved in trifluoroacetic acid (5 mL) andstirred overnight. The reaction was then heated to 50° C. for 3 h andconcentrated to afford the bisTFA salt of the title compound (0.11 g).MS 233.3 (M+1).

3-Piperidin-4-yl-3,4-dihydropyrido[3,2-d]pyrimidin-2(1H-one

Step A. 3-[(2,4-Dimethoxybenzyl)amino]pyridine-2-carbonitrile

2,4-Dimethoxybenzylamine (3.29 g, 19.7 mmol) and triethylamine (1.99 g,19.7 mmol) were added sequentially to a solution of2-cyano-3-fluoropyridine (2.0 g, 16.4 mmol) (Sakamoto et. al., Chem.Pharm. Bull., 1985, 33, 565-71) in N,N-dimethylacetamide (29 mL). Thereaction was heated at 80° C. for 4 h, quenched with water and extractedwith diethyl ether (3×). The combined organic extracts were washedwater, saturated brine, dried over magnesium sulfate and concentrated.The crude product was purified by flash chromatography (silica gel,0-12% ethyl acetate (with 0.1 triethylamine) in dichloromethane gradientelution) to produce the title compound (3.25 g). MS 270.3 (M+1).

Step B. 2-(Aminomethyl)-N-(2,4-dimethoxybenzal)pyridin-3-amine

Lithium aluminum hydride (1.0 M in THF, 13.3 mL, 13.3 mmol) was addedslowly to a solution of3-[(2,4-dimethoxybenzyl)amino]pyridine-2-carbonitrile (3.25 g, 12.1mmol) in tetrahydrofuran (40 mL) at 0° C. The reaction was warmed toroom temperature and stirred for 4 h. The reaction was carefullyquenched with a saturated aqueous solution of sodium sulfate, filteredwith copious dichloromethane and concentrated to produce the titlecompound (2.68 g). MS 274.3 (M+1).

Step C. tert-Butyl4-[({3-[(2,4-dimethoxybenzyl)amino]pyridin-2-yl}methyl)amino]piperidine-1-carboxylate

Sodium triacetoxyborohydride (1.16 g, 5.49 mmol) and acetic acid (0.22g, 3.66 mmol) were added to a solution of a portion of the material formStep B (1.72 g, 3.66 mmol) and N-(t-butoxycarbonyl)-4-piperidone (0.88g, 4.39 mmol) in dichloroethane (20 mL) at room temperature. After 3 h,the reaction was washed with saturated aqueous sodium bicarbonate, driedover sodium sulfate, the solution was filtered and evaporated to givethe product (1.72 g). MS 457.3 (M+1).

Step D. tert-Butyl4-[1-(2,4-dimethoxybenzyl)-2-oxo-1,4-dihydropyrido[3,2-d]pyrimidin-3(2H)-yl]piperidine-1-carboxylate

Carbonyldiimidazole (1.22 g, 7.53 mmol) was added to a solution of thematerial from Step C in dimethylformamide (20 mL) and the reaction washeated to 150° C. overnight. The reaction was diluted with water andextracted with dichloromethane, and the organic phase dried over sodiumsulfate. The crude product was purified by chromatography (silica gel,30 to 100% ethyl acetate in methylene chloride gradient elution), whichgave the title compound (0.10 g). MS 483.3 (M+1).

Step E. 3-Piperidin-4-yl-3,4-dihydropylido[3,2-d]pyrimidin-2(1H)-one

tert-Butyl4-[1-(2,4-dimethoxybenzyl)-2-oxo-1,4-dihydropyrido[3,2-d]pyrimidin-3(2H)-yl]piperidine-1-carboxylate(0.10 g, 0.21 mmol) was dissolved in trifluoroacetic acid (5 mL) andstirred overnight. The reaction was concentrated to afford the bis-TFAsalt of the title compound (0.048 g). MS 233.2 (M+1).

(3R,6S)-3-Amino-1-(2-methoxyethyl)-6-phenylazepan-2-one Step A:2-Bromo-N-(2,4-dimethoxybenzyl)prop-2-en-1-amine

Triethylamine (16.0 mL, 114 mmol) was added to a solution of2,4-dimethoxybenzylamine hydrochloride (11.1 g, 54.5 mmol) and2,3-dibromopropene (10.9 g, 54.5 mmol) in dichloromethane (200 mL).After 18 h, water was added and the mixture was extracted withdichloromethane (3×). The combined organic extracts were washed withsaturated brine, dried over magnesium sulfate, filtered andconcentrated. Purification by silica gel chromatography [100%dichloromethane→95% dichloromethane/5% (10% ammoniumhydroxide/methanol)] gave the title compound (7.85 g).

Step B: Benzyl(1R)-1-{[(2-bromopro-2-enyl)(2,4-dimethoxybenzyl)amino]carbonyl}but-3-enylcarbamate

1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (55 mg,0.285 mmol) was added to a solution of2-bromo-N-(2,4-dimethoxybenzyl)prop-2-en-1-amine (73 mg, 0.256 mmol) and(2R)-2-{[(benzyloxy)carbonyl]amino}pent-4-enoic acid (71 mg, 0.285 mmol)in dichloromethane (5 mL). After 18 h the mixture was concentrated.Purification by silica gel chromatography (5% ethyl acetate/hexanes→30%ethyl acetate/hexanes) gave the title compound (77 mg). MS 517 (M+1).

Step C: Benzyl(1R)-1-{[(2,4-dimethoxybenzyl)(2-phenylprop-2-enyl)amino]carbonyl}but-3-enylcarbamate

Tetrakis(triphenylphosphine)palladium(0) (1.11 g, 0.962 mmol) was addedto a solution of benzyl(1R)-1-{[(2-bromoprop-2-enyl)(2,4-dimethoxybenzyl)amino]carbonyl}but-3-enylcarbamate(2.49 g, 4.81 mmol), phenylboronic acid (0.65 g, 5.29 mmol) and sodiumcarbonate (2M in water; 4.81 mL, 9.63 mmol) in tetrahydrofuran (54 mL)and water (20 mL), and the mixture heated to 60° C. After 1 h, themixture was allowed to cool to ambient temperature and extracted withdichloromethane (3×). The combined organic extracts were washed withsaturated brine, dried over magnesium sulfate, filtered andconcentrated. Purification by silica gel chromatography (5% ethylacetate/hexanes→30% ethyl acetate/hexanes) gave the title compound (2.02g). MS 515 (M+1).

Step D: Benzyl(3R)-1-(2,4-dimethoxybenzyl)-2-oxo-6-phenyl-2,3,4,7-tetrahydro-1H-azepin-3-ylcarbamate

[1,3-bis-(2,4,6-trimethylphenyl-2-imidazolidinylidene)dichloro(phenylmethylene)-(tricyclohexylphosphine)ruthenium](Grubbs second generation catalyst) (0.68 g, 0.79 mmol) was added to asolution of benzyl(1R)-1-{[(2,4-dimethoxybenzyl)(2-phenylprop-2-enyl)amino]carbonyl}but-3-enylcarbamate(2.02 g, 3.93 mmol) in dichloromethane (395 mL) and heated to 40° C.After 40 h, the mixture was allowed to cool to ambient temperature andconcentrated. Purification by silica gel chromatography (5% ethylacetate/hexanes→30% ethyl acetate/hexanes) gave the title compound (1.00g). MS 487 (M+1). ¹H NMR (500 MHz, CDCl₃) δ 7.39-7.31 (m, 5H), 7.26-7.19(m, 3H), 7.17 (d, J=8.3 Hz, 1H), 6.99 (d, J=7.1 Hz, 2H), 6.41 (dd,J=8.3, 2.0 Hz, 1H), 6.33 (s, 1H), 6.22 (d, J=6.4 Hz, 1H), 5.77-5.76 (m,1H), 5.16-5.09 (m, 3H), 4.82 (d, J=14.7 Hz, 1H), 4.65 (dd, J=17.6, 2.7Hz, 1H), 4.54 (d, J=14.4 Hz, 1H), 3.93 (d, J=17.6 Hz, 1H), 3.77 (s, 3H),3.64 (s, 3H), 2.91-2.86 (m, 1H), 2.42-2.36 (m, 1H).

Step E: Benzyl(3R)-2-oxo-6-phenyl-2,3,4,7-tetrahydro-1H-azepin-3-ylcarbamate

A solution of L-methionine (2.56 g, 17.2 mmol) in trifluoroacetic acid(15 mL) was added to a solution of benzyl(3R)-1-(2,4-dimethoxybenzyl)-2-oxo-6-phenyl-2,3,4,7-tetrahydro-1H-azepin-3-ylcarbamate(0.84 g, 1.72 mmol) in dichloromethane (20 mL). After 18 h, the mixturewas concentrated and water was added. The mixture was extracted withethyl acetate, washed with water (2×), saturated aqueous sodiumbicarbonate (2×), saturated brine, dried over magnesium sulfate,filtered and concentrated. Purification by silica gel chromatography (5%ethyl acetate/hexanes→50% ethyl acetate/hexanes) gave the title compound(0.44 g). MS 337 (M+1).

Step F: tert-Butyl (3R,6S)-2-oxo-6-phenylazepan-3-ylcarbamate

10% Palladium on carbon (75 mg) was added to a solution of benzyl(3R)-2-oxo-6-phenyl-2,3,4,7-tetrahydro-1H-azepin-3-ylcarbamate (596 mg,1.77 mmol) and di-tert-butyl dicarbonate (773 mg, 3.54 mmol) in ethylacetate (30 mL). The reaction vessel is evacuated and back-filled withnitrogen (3×), then back-filled with hydrogen (1 atm). After 2 h, themixture was filtered and concentrated. Purification by silica gelchromatography (30% ethyl acetate/hexanes→50% ethyl acetate/hexanes)gave the title compound (289 mg).

Step G: tert-Butyl(3R,6S)-1-(2-methoxyethyl)-2-oxo-6-phenylazepan-3-ylcarbamate

Sodium hydride (60% dispersion in mineral oil; 6.2 mg, 0.158 mmol) wasadded to a solution of tert-butyl(3R,6R)-2-oxo-6-phenylazepan-3-ylcarbamate (40 mg, 0.131 mmol) and2-bromoethyl methyl ether (0.013 mL, 0.138 mmol) inN,N-dimethylformamide (2 mL) at 0° C. After addition, the mixture wasallowed to warm to ambient temperature. After 4 h, the reaction wasquenched with water and the mixture was extracted with ethyl acetate.The organic layer was washed with water (3×), saturated brine, driedover magnesium sulfate, filtered and concentrated. Purification bysilica gel chromatography (5% ethyl acetate/hexanes→30% ethylacetate/hexanes) gave the title compound (41 mg). MS 363 (M+1).

Step H: (3R,6S)-3-Amino-1-(2-methoxyethyl)-6-phenylazepan-2-one

Trifluoroacetic acid (2.5 mL) was added to a solution of tert-butyl(3R,6S)-1-(2-methoxyethyl)-2-oxo-6-phenylazepan-3-ylcarbamate (41 mg,0.113 mmol) in dichloromethane (5 mL). After 1 h, the solution wasconcentrated. Saturated aqueous sodium bicarbonate solution was addedand the mixture was extracted with dichloromethane (3×). The combinedorganic extracts were washed with saturated brine, dried over magnesiumsulfate, filtered and concentrated. MS 263 (M+1). ¹H NMR (500 MHz,CDCl₃) δ 7.32 (t, J=7.3 Hz, 2H), 7.25-7.22 (m, 1H), 7.18 (d, J=8.3 Hz,2H), 3.83-3.76 (m, 3H), 3.56-3.49 (m, 3H), 3.35 (s, 3H), 3.34-3.30 (m,1H), 2.77-2.72 (m, 1H), 2.13-2.10 (m, 1H), 2.03-1.94 (m, 2H), 1.74-1.68(m, 1H).

Essentially following the procedures outlined for the preparation ofIntermediate 14, the Intermediates in Table I-1 were prepared. TABLE I-1

Intermediate C-3 C-6 R¹ MS (M+1) 15 R S H 205 16 R R H 205 17 R S CH₃219 18 R S CH₂CH₃ 233 19 R S CH₂CF₃ 287 20 R S CH₂CO₂CH₃ 277 21 R S(CH₂)₂OCH₂CH₃ 277 22 R S CH₂CN 244 23 R S

259 24 R S

291.1 25 R S CH₂CH₂F 251.1 26 R S CH₂CHF₂ 269.1 27 R S CH₂CHCF₂ 281 28 RS

295 29 R S

296 30 R S

289 31 R S

289 32 R S

291 33 R S

277 34 R S

279 35 R S

311 36 R S (CH₂)₂OCF₃ 317 37 R S

289 38 R S

263.2 39 R S

289 40 R S

317.1 41 R S Ph 281 42 R S

277.2

(3R)-3-Amino-6-(4-hydroxyphenyl)azepan-2-one

Step A: Benzyl(3R)-6-bromo-1-(2,4-dimethoxybenzyl)-2-oxo-2,3,4,7-tetrahydro-1H-azepin-3-ylcarbamate

[1,3-bis-(2,4,6-trimethylphenyl-2-imidazolidinylidene)dichloro(phenylmethylene)-(tricyclohexylphosphine)ruthenium](Grubbs second generation catalyst) (1.78 g, 2.05 mmol) was added to asolution of benzyl (1R)-1-{[(2-bromoprop-2-enyl)(2,4-dimethoxybenzyl)amino]carbonyl}but-3-enylcarbamate (5.29 g, 10.2 mmol) indichloromethane (1000 mL) and heated to 40° C. After 18 h, the mixturewas allowed to cool to ambient temperature and concentrated.Purification by silica gel chromatography (5% ethyl acetate/hexanes→30%ethyl acetate/hexanes) gave the title compound (0.79 g). MS 489 (M+1).¹H NMR (500 MHz, CDCl₃) δ 7.36-7.35 (m, 4H), 7.33-7.30 (m, 1H),7.17-7.15 (m, 1H), 6.46-6.43 (m, 2H), 6.13 (d, J=6.1 Hz, 1H), 6.04-6.03(m, 1H), 5.13-5.07 (m, 2H), 4.93-4.88 (m, 1H), 4.75 (d, J=14.4 Hz, 1H),4.64-4.60 (m, 1H), 4.47 (d, J=14.4 Hz, 1H), 3.86 (d, J=18.3 Hz, 1H),3.81 (s, 3H), 3.80 (s, 3H), 2.68-2.63 (m, 1H), 2.24-2.05 (m, 1H).

Step B: Benzyl(3R)-6-bromo-2-oxo-2,3.4,7-tetrahydro-1H-azepin-3-ylcarbamate

A solution of L-methionine (274 mg, 1.84 mmol) in trifluoroacetic acid(5 mL) was added to a solution of benzyl(3R)-6-bromo-1-(2,4-dimethoxybenzyl)-2-oxo-2,3,4,7-tetrahydro-1H-azepin-3-ylcarbamate(90 mg, 0.184 mmol) in dichloromethane (5 mL). After 18 h, the mixturewas concentrated. Purification by reverse phase HPLC (C-18, 95%water/acetonitrile→5% water/acetonitrile with 0.1% trifluoroacetic acid)gave the title compound (17 mg). MS 339 (M+1).

Step C: Benzyl(3R)-6-(4-hydroxyphenyl)-2-oxo-2,3,4,7-tetrahydro-1H-azepin-3-ylcarbamate

Palladium acetate (1 mg, 0.003 mmol) was added to a solution of benzyl(3R)-6-bromo-2-oxo-2,3,4,7-tetrahydro-1H-azepin-3-ylcarbamate (18 mg,0.053 mmol), 4-hydroxyphenylboronic acid (9 mg, 0.064 mmol), sodiumcarbonate (2M in water; 0.066 mL, 0.133 mmol) and trisodium3-[bis(3-sulfonatophenyl)phosphino]benzenesulfonate (5 mg, 0.088 mmol)in N,N-dimethylformamide (0.45 mL) and water (0.15 mL) and heated to 80°C. After 1.5 h, the mixture was allowed to cool to ambient temperatureand filtered. Purification by reverse phase HPLC (C-18, 95%water/acetonitrile→5% water/acetonitrile with 0.1% trifluoroacetic acid)gave the title compound (15 mg). MS 353 (M+1).

Step D: (3R)-3-Amino-6-(4-hydroxyphenyl)azepan-2-one

10% Palladium on carbon (10 mg) was added to a solution of benzyl(3R)-6-(4-hydroxyphenyl)-2-oxo-2,3,4,7-tetrahydro-1H-azepin-3-ylcarbamate(15 mg, 0.043 mmol) in toluene (5 mL) and methanol (1 mL). The reationvessel is evacuated and back-filled with nitrogen (3×), then back-filledwith hydrogen (1 atm). After 18 h, the mixture was filtered andconcentrated. MS 221 (M+1).

Essentially following the procedures outlined for the preparation ofIntermediate 43, the Intermediates in Table 1-2 were prepared. Compoundsalong the route to the Intermediates in Table 1-2, can be furtherprocessed (e.g. alkylation of N1) according to those skilled in the artfollowing essentially the same procedures as outlined above to affordanother set of intermediates. TABLE I-2

Intermediate C-3 C-6 R¹ MS (M=1) 44 R R or S

223.2 45 R R or S

223.2 46 R R or S

223.2 47 R R or S

241.2 48 R R or S

206.3 49 R R or S

206.3 50 R R or S

206.2 51 R R or S

241.2 52 R R or S

241.2 53 R R or S

273.2 54 R R or S

219.2 55 R R or S

219.2 56 R R or S

219.2

(3R)-3-Amino-6-(2,3-dichlorophenyl)azepan-2-one

Step A. Benzyl (SR orS)-N,N-bis(tert-butoxycarbonyl)-5-(2,3-dichlorophenyl)-6-nitro-D-norleucinate

To a slurry of 1-bromo-2,3-dichlorobenzene (1.46 g, 6.46 mmol) indiethyl ether (10 mL) was added magnesium (0.157 g, 6.46 mmol) and acrystal of iodine. This mixture was refluxed for 3 h, and then cooled toroom temperature. A solution of benzyl(2R,5E)-2-[bis(tert-butoxycarbonyl)amino]-6-nitrohex-5-enoate (0.50 g,1.08 mmol) in diethyl ether (10 mL) was cooled to 0° C., and 2.0 μL ofthe Grignard solution prepared above was added. After 1 and 2 h,respectively, 2.0 and 1.0 mL of the Grignard solution was added. Thereaction was quenched with a saturated aqueous solution of ammoniumchloride, the phases separated and the organic phase washed withsaturated aqueous sodium potassium tartrate and brine. The combinedorganics were dried over magnesium sulfate, filtered and concentrated togive a residue that was purified by silica gel chromatography (0%→3%methanol/dichloromethane) to give the title compound (0.52 g). MS 411.0(M+1-2Boc).

Step B. BenzylN²,N²-bis(tert-butoxycarbonyl)-5-(2,3-dichlorophenyl)-D-lysinate

To an EtOH rinsed (4×5 mL) slurry of Raney Ni (1 mL) was added asolution of benzyl (SR orS)-N,N-bis(tert-butoxycarbonyl)-5-(2,3-dichlorophenyl)-6-nitro-D-norleucinate(0.52 g, 0.85 mmol) in EtOH (5 mL). This slurry was hydrogenated under aballoon of hydrogen for 2 h. The reaction was filtered through Celitewith more EtOH and concentrated to afford the title compound (0.45 g).MS 581 (M+1).

Step C. (3R)-3-Amino-6-(2,3-dichlorophenyl)azepan-2-one

To a solution benzylN²,N²-bis(tert-butoxycarbonyl)-5-(2,3-dichlorophenyl)-D-lysinate (0.45g, 0.77 mmol) in MeOH (4 mL) and water (2 mL) was added 1N NaOH (3.1 mL,3.1 mmol). This solution was heated to 40° C. for 6 h, then neutralizedwith 1N HCl and concentrated. To a solution of this residue in DCM (10mL) were added EDC (0.19 g, 0.97 mmol) and HOAT (53 mg, 0.39 mmol)followed by triethylamine (0.32 mL, 0.73 mmol). After 2 h, NaHCO₃ wasadded, the layers separated and the aqueous phase backwashed with DCM.The combined organics were dried over magnesium sulfate, filtered andconcentrated. This residue was purified by silica gel chromatography(0.5%→10% MeOH/DCM) to give di-tert-butyl[(3R)-6-(2,3-dichlorophenyl)-2-oxoazepan-3-yl]imidodicarbonate (300 mg).MS 473 (M+1). Standard deprotection of a portion of this material gavethe title product. MS 273 (M+1).

Essentially following the procedures outlined for the preparation ofIntermediate 57, the Intermediates in Table 1-3 were prepared. Compoundsalong the route to the Intermediates in Table 1-3, can be furtherprocessed (e.g. alkylation of N1) according to those skilled in the artfollowing essentially the same procedures as outlined above to affordanother set of intermediates. TABLE I-3

Intermediate C-3 C-6 R¹ MS (M+1) 58 R R or S

239.1 59 R R or S

439.2 diBoc 60 R R or S

211.3 61 R R or S

371.3 diBoc 62 R R or S

219.2 63 R R or S

257.2

(2S,6R)-6-Amino-4-(cyclopropylmethyl)-2-phenyl-1,4-oxazepan-5-one

Step A. tert-Butylcyclopropylmethyl-(2S)-2-hydroxy-2-phenylethyl]carbamate

(S)-Styrene oxide (4.83 g, 40.3 mmol) and cyclopropanemethylamine (4.00g, 56.4 mmol) were dissolved in isopropyl alcohol (100 mL) and heated toreflux. After 8 h, the reaction was allowed to cool to ambienttemperature and concentrated. Triethylamine (5.61 mL, 40.3 mmol) wasadded to a solution of the crude amine and di-tert-butyl dicarbonate(8.78 g, 40.3 mmol) in dichloromethane (100 mL). After 18 h, water wasadded, and the mixture was extracted with ethyl acetate. The organiclayer was washed with brine, dried over magnesium sulfate, filtered andconcentrated. Purification by silica gel chromatography (5% ethylacetate/hexanes→20% ethyl acetate/hexanes) gave the title compound (5.48g).

Step B. MethylN-[(benzyloxy)carbonyl]-O-{(1S)-2-[(tert-butoxycarbonyl)(cyclopropylmethyl)amino]-1-phenylethyl}-D-serinate

Boron trifluoride diethyl etherate (0.10 mL, 0.84 mmol) was added to asolution of tert-butylcyclopropylmethyl[(2S)-2-hydroxy-2-phenylethyl]carbamate (2.45 g, 8.39mmol) and 1-benzyl 2-methyl (2R)-aziridine-1,2-dicarboxylate (1.97 g,8.39 mmol) in chloroform (20 mL). After 3 h, the reaction wasconcentrated. Purification by silica gel chromatography (100%hexanes→30% ethyl acetate/hexanes) gave the title compound (1.21 g).

Step C. N-[(Benzyloxy)carbonyl]-O-{(1S)-2-[(tert-butoxycarbonyl)(cyclopropylmethyl)amino]-1-phenylethyl}-D-serine

Aqueous sodium hydroxide (1N; 3.81 mL, 3.81 mmol) was added to asolution of methylN-[(benzyloxy)carbonyl]-O-{(1S)-2-[(tert-butoxycarbonyl)(cyclopropylmethyl)amino]-1-phenylethyl}-D-serinate(1.30 g, 2.46 mmol) in tetrahydrofuran (20 mL). After 18 h, aqueoushydrochloric acid (1N; 3.81 mL, 3.81 mmol) was added. The mixture wasextracted with dichloromethane (3×), and the combined organic extractswere dried over magnesium sulfate, filtered, and concentrated to givethe title compound. (1.27 g) MS 535 (M+Na).

Step D. Benzyl(2S,6R)-4-(cyclopropylmethyl)-5-oxo-2-phenyl-1,4-oxazepan-6-ylcarbamate

Trifluoroacetic acid (5.0 mL) was added to a solutionN-[(benzyloxy)carbonyl]-O-{(1S)-2-[(tert-butoxycarbonyl)(cyclopropylmethyl)amino]-1-phenylethyl}-D-serine (1.27 g, 2.47 mmol) indichloromethane (15 mL). After 2 h, the mixture was concentrated andazeotroped with toluene (3×) to give the crude amine. Diphenylphosphorylazide (1.07 ml, 4.95 mmol) was added to a solution of the crude amineand 4-methylmorpholine (0.82 mL, 7.41 mmol) in N,N-dimethylformamide(100 mL). After 18 h, the mixture was concentrated and water was added.The mixture was extracted with ethyl acetate, and the organic layer waswashed with water (2×) and saturated brine, dried over magnesiumsulfate, filtered, and concentrated. Purification by silica gelchromatography (5% ethyl acetate/hexanes→50% ethyl acetate/hexanes) gavethe title compound (0.426 g). MS 395 (M+1).

Step E.(2S,6R)-6-Amino-4-(cyclopropylmethyl)-2-phenyl-1,4-oxazepan-5-one

10% Palladium on carbon (20 mg) was added to a solution(2S,6R)-6-amino-4-(cyclopropylmethyl)-2-phenyl-1,4-oxazepan-5-one (179mg, 0.454 mmol) in ethanol (15 mL). The reaction vessel was evacuatedand back-filled with nitrogen (3×), then back-filled with hydrogen (1atm). After 18 h, the mixture was filtered and concentrated to give thetitle compound (113 mg). MS 261 (M+1). ¹H NMR (500 MHz, CDCl₃) δ7.40-7.31 (m, 5H), 4.53 (d, J=8.5 Hz, 1H), 4.10-4.03 (m, 2H), 3.90 (dd,J=15.9, 7.1 Hz, 1H), 3.80-3.65 (m, 2H), 3.36 (d, J=15.9 Hz, 1H), 3.03(dd, J=13.9, 6.6 Hz, 1H), 1.06-1.01 (m, 1H), 0.64-0.53 (m, 2H),0.33-0.25 (m, 2H).

(2S,6R)-6-Amino-2-(2,3-difluorophenyl)-4-(2,2,2-trifluoroethyl)-1,4-oxazepan-5-one

The title compound was prepared using a similar procedure toIntermediate 64. MS 325 (M+1).

tert-Butyl[1-(2-methoxyethyl)-2-oxo-6-phenylazepan-3-yl]acetate

Step A. 1-(2-Methoxyethyl)-6-phenylazepan-2-one

Sodium hydride (60% dispersion in mineral oil; 0.32 g, 8.03 mmol) wasadded to a solution of 6-phenylazepan-2-one (0.76 g, 4.02 mmol) inN,N-dimethylformamide (15 mL) at 0° C., followed by the addition of2-bromoethyl methyl ether (0.837 g, 6.03 mmol), and the mixture wasallowed to warm to ambient temperature. After 21 h, water was added andthe mixture was extracted with ethyl acetate (3×). The combined organicextracts were washed with water (3×), saturated brine, dried over sodiumsulfate, filtered and concentrated. MS 248 (M+1).

Step B. tert-Butyl[1-(2-methoxyethyl)-2-oxo-6-phenylazepan-3-yl]acetate

Lithium diisopropylamide (1.8 M in heptane/tetrahydrofuran/ethylbenzene;0.58 g, 5.41 mmol) was added to a solution of1-(2-methoxyethyl)-6-phenylazepan-2-one (1.03 g, 4.16 mmol) intetrahydrofuran (40 mL) at −78° C. After 2 h, tert-butylbromoacetate wasadded. After an additional 1.5 h, the reaction was quenched withmethanol and allowed to warm to ambient temperature and concentrated.Purification by reverse phase HPLC (C-18, 95% water/acetonitrile→5%water/acetonitrile with 0.1% trifluoroacetic acid) gave 450 mg (cisisomer) and 350 mg (trans isomer) of the title compound. MS 362 (M+1).cis isomer: ¹H NMR (500 MHz, CDCl₃) δ 7.29 (t, J=7.6 Hz, 2H), 7.26 (m,1H), 7.22-7.20 (m, 2H), 4.04 (br d, J=15.2 Hz, 1H), 3.84 (dt, J=13.9,4.9 Hz, 1H), 3.51 (dd, J=15.4, 3.9 Hz, 1H), 3.40-3.35 (m, 1H), 3.30-3.21(m, 2H), 3.24 (s, 3H), 3.02-3.00 (m, 1H), 2.84 (dd, J=16.4, 7.6 Hz, 1H),2.68-2.66 (m, 1H), 2.33 (dd, J=16.4, 6.8 Hz, 1H), 2.11-2.07 (m, 1H),2.05-1.95 (m, 1H), 1.80-1.76 (m, 2H), 1.46 (s, 9H). trans isomer: ¹H NMR(500 MHz, CDCl₃) δ 7.32 (t, J=7.3 Hz, 2H), 7.24-7.21 (m, 1H), 7.18 (d,J=7.1 Hz, 2H), 3.96 (dd, J=14.9, 10.0 Hz, 1H), 3.82-3.77 (m, 1H),3.56-3.46 (m, 2H), 3.43-3.38 (m, 1H), 3.34 (s, 3H), 3.30 (d, J=15.1 Hz,1H), 3.20-3.15 (m, 1H), 2.85 (dd, J=16.6, 7.8 Hz, 1H), 2.78 (br t, 1H),2.26 (dd, J=16.6, 6.6 Hz, 1H), 2.10 (br d, J=22.7, 9.3 Hz, 1H),1.77-1.73 (m, 1H), 1.62-1.59 (m, 1H), 1.46 (s, 9H).

tert-Butyl[1-(cyclopropylmethyl)-2-oxo-6-phenylazepan-3-yl]acetate

The title compounds (both cis and trans) were prepared withcyclopropylmethyl bromide and 6-phenylazepan-2-one using a similarprocedure to Intermediate 66. MS 358 (M+1).

(3R,6S)-3-Amino-6-(2,3-difluorophenyl)azepan-2-one

Step A. 2-Bromo-N-(2,4-dimethoxybenzyl)prop-2-en-1-amine

Triethylamine (16.0 mL, 114 mmol) was added to a solution of2,4-dimethoxybenzylamine hydrochloride (11.1 g, 54.5 mmol) and2,3-dibromopropene (10.9 g, 54.5 mmol) in dichloromethane (200 mL).After 18 h, water was added and the mixture was extracted withdichloromethane (3×). The combined organic extracts were washed withsaturated brine, dried over magnesium sulfate, filtered andconcentrated. Purification by silica gel chromatography [100%dichloromethane→95% dichloromethane/5% (10% ammoniumhydroxide/methanol)] gave the title compound (7.85 g).

Step B. Benzyl (1R)-1-{[(2-bromoprop-2-enyl)(2,4-dimethoxybenzal)amino]carbonyl}but-3-enylcarbamate

1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (55 mg,0.285 mmol) was added to a solution of2-bromo-N-(2,4-dimethoxybenzyl)prop-2-en-1-amine (73 mg, 0.256 mmol) and(2R)-2-{[(benzyloxy)carbonyl]amino}pent-4-enoic acid (71 mg, 0.285 mmol)in dichloromethane (5 mL). After 18 h the mixture was concentrated.Purification by silica gel chromatography (5% ethyl acetate/hexanes→30%ethyl acetate/hexanes) gave the title compound (77 mg). MS 517 (M+1).

Step C. Benzyl(1R)-1-{[[2-(2,3-difluorophenyl)prop-2-enyl](2,4-dimethoxybenzyl)amino]carbonyl]but-3-enylcarbamate

Dichloro [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloromethaneadduct (0.726 g, 0.889 mmol) was added to a solution of benzyl(1R)-1-{[(2-bromoprop-2-enyl)(2,4-dimethoxybenzyl)amino]carbonyl}but-3-enylcarbamate(9.2 g, 17.8 mmol), 2,3-difluorophenylboronic acid (2.95 g, 18.7 mmol)and sodium carbonate (2M in water; 19.6 mL, 39.1 mmol) inN,N-dimethylformamide (60 mL) and the mixture was heated to 75° C. After2 h, the mixture was allowed to cool to ambient temperature andextracted with dichloromethane (3×). The combined organic extracts werewashed with saturated brine, dried over magnesium sulfate, filtered andconcentrated. Purification by silica gel chromatography (5% ethylacetate/hexanes→55% ethyl acetate/hexanes) gave the title compound (6.8g). MS 551.2 (M+1).

Step D. Benzyl(3R)-6-(2,3-difluorophenyl)-1-(2,4-dimethoxybenzal)-2-oxo-2,3,4,7-tetrahydro-1H-azepin-3-ylcarbamate

[1,3-bis-(2,4,6-Trimethylphenyl-2-imidazolidinylidene)dichloro(phenylmethylene)-(tricyclohexylphosphine)ruthenium](Grubbs second generation catalyst) (2.62 g, 3.09 mmol) was added to asolution of benzyl(1R)-1-{[[2-(2,3-difluorophenyl)prop-2-enyl](2,4-dimethoxybenzyl)amino]carbonyl}but-3-enylcarbamate(6.8 g, 12.35 mmol) in dichloromethane (1800 mL) and the solution washeated to 40° C. After 48 h, additional catalyst was added (0.52 g, 0.61mmol) and the reaction continued to heat at 40° C. for an additional 48h. The mixture was allowed to cool to ambient temperature andconcentrated. Purification by silica gel chromatography (5% ethylacetate/hexanes→55% ethyl acetate/hexanes) gave the title compound (3.71g). MS 523.1 (M+1).

Step E. Benzyl(3R)-6-(2,3-difluorophenyl)-2-oxo-2,3,4,7-tetrahydro-1H-azepin-3-ylcarbamate

Trifluoroacetic acid (60 mL) was added to a solution of benzyl(3R)-6-(2,3-difluorophenyl)-1-(2,4-dimethoxybenzyl)-2-oxo-2,3,4,7-tetrahydro-1H-azepin-3-ylcarbamate(3.70 g, 7.08 mmol) in dichloromethane (40 mL). After 18 h, the mixturewas concentrated at 25° C., methanol (150 mL) was added, and theprecipitate filtered. The filtrate was concentrated, diluted withdichloromethane (100 mL), washed with water (2×), saturated aqueoussodium bicarbonate (2×), saturated brine, dried over magnesium sulfate,filtered and concentrated. Purification by silica gel chromatography (5%ethyl acetate/hexanes→65% ethyl acetate/hexanes) gave the title compound(1.75 g). MS 373.1 (M+1).

Step F. tert-Butyl(3R,6S)-6-(2,3-difluorophenyl)-2-oxoazepan-3-ylcarbamate

10% Palladium on carbon (700 mg) was added to a solution of benzyl(3R)-6-(2,3-difluorophenyl)-2-oxo-2,3,4,7-tetrahydro-1H-azepin-3-ylcarbamate(2.6 g, 6.98 mmol) and di-tert-butyl dicarbonate (5.03 g, 23.0 mmol) intoluene (200 mL). The reaction vessel was evacuated and back-filled withnitrogen (3×), then back-filled with hydrogen (I atm). After 24 h, themixture was filtered and concentrated. Purification by preparativereverse phase chromatography (DeltaPak C18, 15, 47 mm×300 mm, 70 mL/min:80% H₂O/NH₄OAc: 20% CH₃CN to 100% CH₃CN over 60 min) afforded the puretrans title compound (1.2 g). MS 341.2 (M+1). ¹H NMR (500 MHz, CDCl₃) δ7.07-7.04 (m, 2H), 6.91-6.89 (m, 1H), 6.04 (br s, 1H), 5.93 (d, J=5.6Hz, 1H), 4.46 (dd, J=10.5, 4.6 Hz, 1H), 3.65-3.59 (m, 1H), 3.21 (dd,J=15.1, 7.3 Hz, 1H), 3.05-3.00 (m, 1H), 2.25-2.20 (m, 1H), 2.17-2.10 (m,2H), 1.79-1.71 (m, 1H), 1.46 (s, 9H).

Step G. (3R,6S)-3-Amino-6-(2,3-difluorophenyl)azepan-2-one

Trifluoroacetic acid (4 mL) was added to a solution of tert-butyl(3R,6S)-6-(2,3-difluorophenyl)-2-oxoazepan-3-ylcarbamate (82 mg, 0.241mmol) in dichloromethane (4 mL). After 1 h, the solution wasconcentrated. Saturated aqueous sodium bicarbonate solution was addedand the mixture was extracted with dichloromethane (3×). The combinedorganic extracts were washed with saturated brine, dried over magnesiumsulfate, filtered and concentrated. MS 241.0 (M+1)

Alternatively, Intermediate 68 can be made in the following manner:

Step H. 1-Benzyl 5-methyl N,N-bis(tert-butoxycarbonyl)-D-glutamate

To a solution of Boc-D-Glu-OBn (50.0 g, 148.2 mmol) in DCM (400 ml) andMeOH (100 ml) was added trimethylsilyldiazomethane (88.9 mL of 2.0 Msolution in hexanes, 117.8 mmol) at 0° C. dropwise via an additionfunnel. After 60 min the reaction was concentrated. This residue wasdiluted with CH₃CN (400 mL) and (Boc)₂O (48.5 g, 222.3 mmol) was addedfollowed by DMAP (18.1 g, 14.8 mmol). After 24 h the reaction wasconcentrated and purified by silica gel chromatography (10%→60% ethylacetate/hexanes) to give the title compound (48.20 g, 72%). MS 252.2(M+1-2Boc).

Step I. Benzyl(2R,5E)-2-[bis(tert-butoxycarbonyl)amino]-6-nitrohex-5-enoate

To a −78° C. of 1-benzyl 5-methylN,N-bis(tert-butoxycarbonyl)-D-glutamate (48.2 g, 106.8 mmol) in Et₂O(400 mL), was added DIBAL (133.4 mL of 1.0 M solution in toluene, 133.4mmol) slowly so as not to let the internal temperature exceed −65° C.After 15 min, 20 mL more of DIBAL was added. After stirring foradditional 20 min, water (300 mL) was added and the reaction was warmedto room temperature and stirred for 30 min. This mixture was furtherdiluted with Et₂O and H₂O, the layers separated and the aqueous phaseextracted with more Et₂O. The combined organics extracts were washedwith a saturated aqueous solution of sodium potassium tartrate (2×),brine, dried over magnesium sulfate, filtered and concentrated to givebenzyl N,N-bis(tert-butoxycarbonyl)-5-oxo-D-norvalinate (44.4 g) whichwas carried directly into the next step. MS 444.1 (M+Na). This materialwas dissolved in toluene (310 mL) and nitromethane (57.1 mL, 1.05 mol)and 1,1,3,3-tetramethylguanidine (1.3 mL, 10.5 mmol) were added at 0° C.After stirring for 30 min the nitroaldol reaction was complete, somethanesulfonyl chloride (12.2 mL, 158 mmol) was added followedtriethylamine (22.0 mL, 158 mmol) at 0° C. and the reaction was allowedto warm to RT. After 1 h, 4 mL MsCl and 5.5 mL triethylamine were added.After stirring for an additional 30 min the mixture was diluted withEt₂O and NaHCO₃, the phases separated and the aqueous layer backwashedwith another portion of Et₂O. The combined organics were dried overmagnesium sulfate, filtered and concentrated to give a residue that waspurified by silica gel chromatography (5%→50% ethyl acetate/hexanes) togive the title compound (34.3 g, 70%). MS 487.1 (M+Na).

Step J. Benzyl(5S)-N,N-bis(tert-butoxycarbonyl)-5-(2,3-difluoropheiyl)-6-nitro-D-norleucinate

A solution of benzyl(2R,5E)-2-[bis(tert-butoxycarbonyl)amino]-6-nitrohex-5-enoate (34.0 g,73.2 mmol), 2,3-difluorophenylboronic acid (28.9 g, 183.0 mmol) andwater (4.62 mL, 256.2 mmol) in dioxane (240 mL) was degassed with argonfor 15 min. To this solution was added sodium bicarbonate (3.08 g, 36.6mmol), (S)-BINAP (1.28 g, 2.05 mmol) andacetylacetanotobis(ethylene)rhodium(I) (0.472 g, 1.83 mmol). The mixturewas stirred at RT for 2 min then heated to 35° C. After 4 h, 255 mg of(S)-BINAP and 94 mg of acetylacetanotobis(ethylene)rhodium(I) wereadded. After an additional 2 h the reaction was diluted with DCM/NaHCO₃,the layers separated and the aqueous phase was backwashed with anotherportion of DCM. The combined organics were dried over magnesium sulfate,filtered and concentrated to give a residue that was purified by silicagel chromatography (5%→60% ethyl acetate/hexanes) to give the titlecompound (37.0 g, 87%) contaminated with 5%→5R isomer. MS 379.1(M+1-2Boc).

Step K.(5S)-N²,N²-Bis(tert-butoxycarbonyl)-5-(2,3-difluorophenyl)-D-lysine

A solution of benzyl(5S)-N,N-bis(tert-butoxycarbonyl)-5-(2,3-difluorophenyl)-6-nitro-D-norleucinate(15.5 g, 26.8 mmol) and 10% Pd/C (12.0 g) in EtOH (175 mL, SureSeal fromAldrich), was hydrogenated at 55 psi overnight. After 18 h, another 4 gof 10% Pd/C was added and the reaction hydrogenated at 55 psi foranother 18 h. The reaction was filtered through Celite with more EtOHand concentrated to afford the title compound (12.0 g). MS 459.2 (M+1).

Step L. tert-Butyl(3R,6S)-6-(2,3-difluorophenyl)-2-oxoazepan-3-ylcarbamate

To a solution(5S)-N²,²-bis(tert-butoxycarbonyl)-5-(2,3-difluorophenyl)-D-lysine (22.0g, 48.0 mmol) in DCM (700 mL) were added EDC (11.0 g, 57.6 mmol) andHOAT (3.27 g, 24.0 mmol) followed by triethylamine (10.0 mL, 72.0 mmol).After 60 min, NaHCO₃ was added, the layers separated and the aqueousphase backwashed with DCM. The combined organics were dried overmagnesium sulfate, filtered and concentrated. The residue was purifiedby silica gel chromatography (10% MeOH/DCM) to give the cyclizedcompound (18.0 g). A portion of this material (2.60 g, 5.90 mmol) wasdiluted DCM (60 mL) and TFA (1.20 mL, 11.8 mmol) was added. After 1 h,NaHCO₃ was added, the layers separated and the aqueous phase backwashedwith DCM. The combined organics were dried over magnesium sulfate,filtered and concentrated and the residue purified by silica gelchromatography (5%→50% EtOAc/DCM) to give the title compound (1.14 g).MS 341.1 (M+1).

(3R,6S)-3-Amino-6-(2,3-difluorophenyl)-1-[2-(methylthio)ethyl]azepan-2-one

Step A. tert-butyl(3R,6S)-6-(2,3-difluorophenyl)-1-[2-(methylthio)ethyl]-2-oxoazepan-3-ylcarbamate

Sodium hydride (60% dispersion in mineral oil; 40 mg, 0.600 mmol) wasadded to a solution of tert-butyl(3R,6S)-6-(2,3-difluorophenyl)-2-oxoazepan-3-ylcarbamate (170 mg, 0.500mmol) in N,N-dimethylformamide (4 mL) at 0° C. After 5 min the mixturewas cooled to −30° C. and 1-iodo-2-(methylthio)ethane [preparedaccording to known procedures: J. Org. Chem., 1987, 52, 2299-2301 (158mg, 0.782 mmol)] was added. Additional sodium hydride (33 mg, 0.50 mmol)was added and after 4 h excess sodium hydride (33 mg, 0.50 mmol) and1-iodo-2-(methylthio)ethane (75.6 mg, 0.374 mmol) were added. After 3 h,the final portions of sodium hydride (33 mg, 0.50 mmol) and1-iodo-2-(methylthio)ethane (75.6 mg, 0.374 mmol) were added and themixture stirred at −20° C. overnight. The reaction was quenched withwater and the mixture was extracted with ethyl acetate. The organiclayer was washed with water (3×), saturated brine, dried over magnesiumsulfate, filtered and concentrated. Purification by silica gelchromatography (0% ethyl acetate/hexanes→50% ethyl acetate/hexanes) gavethe title compound (77 mg). MS 415 (M+1).

Step B.(3R,6S)-3-Amino-6-(2,3-difluorophenyl)-1-[2-(methylthio)ethyl]azepan-2-one

Trifluoroacetic acid (2 mL) was added to a solution of tert-butyl(3R,6S)-6-(2,3-difluorophenyl)-1-[2-(methylthio)ethyl]-2-oxoazepan-3-ylcarbamate(77 mg, 0.186 mmol) in dichloromethane (10 mL). After 30 min, thesolution was concentrated and azeotroped with toluene (2×). Saturatedaqueous sodium bicarbonate solution was added and the mixture wasextracted with dichloromethane (3×). The combined organic extracts werewashed with saturated brine, dried over magnesium sulfate, filtered andconcentrated. MS 315.2 (M+1).

(3R,6S)-3-Amino-6-(2,3-difluorophenyl)-1-[2-(methylsulfinyl)ethyl]azepan-2-one

Step A. tert-Butyl(3R,6S)-6-(2,3-difluorophenyl)-1-[2-(methylsulfinyl)ethyl]-2-oxoazepan-3-ylcarbamate

Sodium periodate (11.3 mg, 0.053 mmol) was added to a solution oftert-butyl(3R,6S)-6-(2,3-difluorophenyl)-1-[2-(methylthio)ethyl]-2-oxoazepan-3-ylcarbamate(22 mg, 0.053 mmol) in methanol (2 mL) and water (2 mL). After 30 minexcess sodium periodate (22 mg, 0.11 mmol) was added. After 18 h,saturated aqueous sodium carbonate was added and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated aqueous sodium carbonate (3×), saturated brine, dried overmagnesium sulfate, filtered and concentrated to give the title compound.MS 431 (M+1).

Step B.(3R,6S)-3-Amino-6-(2,3-difluorophenyl)-1-[2-(methylsulfinyl)ethyl]azepan-2-one

Trifluoroacetic acid (1 mL) was added to a solution of tert-butyl(3R,6S)-6-(2,3-difluorophenyl)-1-[2-(methylsulfinyl)ethyl]-2-oxoazepan-3-ylcarbamate(23 mg, 0.053 mmol) in dichloromethane (2 mL). After 3 h, the solutionwas concentrated. Saturated aqueous sodium bicarbonate solution wasadded and the mixture was extracted with dichloromethane (3×). Thecombined organic extracts were washed with saturated brine, dried overmagnesium sulfate, filtered and concentrated to give the title compound.MS 331 (M+1).

(3R,6S)-3-Amino-6-(2,3-difluorophenyl)-1-[2-(methylsulfonyl)ethyl]azepan-2-one

Step A. tert-Butyl(3R,6S)-6-(2,3-difluorophenyl)-1-[2-(methylsulfonyl)ethyl]-2-oxoazepan-3-ylcarbamate

Oxone ® ((16.1 mg, 0.11 mmol) was added to a solution of tert-butyl(3R,6S)-6-(2,3-difluorophenyl)-1-[2-(methylthio)ethyl]-2-oxoazepan-3-ylcarbamate(22 mg, 0.053 mmol) in methanol (2 mL) and water (2 mL). After 6 hexcess oxone (32 mg, 0.22 mmol) was added. After 18 h, the reaction wasquenched with aqueous sodium sulfite solution and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated aqueous sodium carbonate (3×), saturated brine, dried overmagnesium sulfate, filtered and concentrated to give the title compound.MS 447 (M+1).

Step B.(3R,6S)-3-Amino-6-(2,3-difluorophenyl)-1-[2-(methylsulfonyl)ethyl]azepan-2-one

Trifluoroacetic acid (1 mL) was added to a solution of tert-butyl(3R,6S)-6-(2,3-difluorophenyl)-1-[2-(methylsulfonyl)ethyl]-2-oxoazepan-3-ylcarbamate(23.7 mg, 0.053 mmol) in dichloromethane (2 mL). After 4 h, the solutionwas concentrated. Saturated aqueous sodium bicarbonate solution wasadded and the mixture was extracted with dichloromethane (3×). Thecombined organic extracts were washed with saturated brine, dried overmagnesium sulfate, filtered and concentrated to give the title compound.MS 347 (M+1).

(3R,6S)-3-Amino-6-(2,3-difluorophenyl)-1-(2-methoxyethyl)azepan-2-one

Step A. tert-Butyl(3R,6S)-6-(2,3-difluorophenyl)-1-(2-methoxyethyl)-2-oxoazepan-3-ylcarbamate

Sodium hydride (60% dispersion in mineral oil; 17.6 mg, 0.264 mmol) wasadded to a solution of tert-butyl(3R,6S)-6-(2,3-difluorophenyl)-2-oxoazepan-3-ylcarbamate (75 mg, 0.220mmol) in N,N-dimethyl formamide (2 mL) at 0° C. After 5 min,2-bromoethyl methyl ether (0.025 mL, 0.264 mmol) was added and themixture was allowed to warm to ambient temperature. After 3 h, thereaction was quenched with water and the mixture was extracted withethyl acetate. The organic layer was washed with water (2×), saturatedbrine, dried over magnesium sulfate, filtered and concentrated to givethe title compound. MS 421 (M+Na).

Step B.(3R,6S)-3-Amino-6-(2,3-difluorophenyl)-1-(2-methoxyethyl)azepan-2-one

Trifluoroacetic acid (2.5 mL) was added to a solution of tert-butyl(3R,6S)-6-(2,3-difluorophenyl)-1-(2-methoxyethyl)-2-oxoazepan-3-ylcarbamate(99 mg, 0.248 mmol) in dichloromethane (5 mL). After 1 h, the solutionwas concentrated and azeotroped with toluene (2×). Saturated aqueoussodium bicarbonate solution was added and the mixture was extracted withdichloromethane (3×). The combined organic extracts were washed withsaturated brine, dried over magnesium sulfate, filtered andconcentrated. MS 299.2 (M+1).

(3R,6S)-3-Amino-6-(2,3-difluorophenyl)-1-(2,2,2-trifluoroethyl)azepan-2-one

Step A: tert-Butyl(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-ylcarbamate

Sodium hydride (60% dispersion in mineral oil; 70.7 mg, 1.06 mmol) wasadded to a solution of tert-butyl(3R,6S)-6-(2,3-difluorophenyl)-2-oxoazepan-3-ylcarbamate (301 mg, 0.884mmol) in N,N-dimethylformamide (7 mL) at −35° C. After 15 min,2,2,2-trifluoroethyl trichloromethanesulfonate (0.314 mL, 1.91 mmol) wasadded and the reaction was stirred at −35° C. After 30 min, anadditional amount of sodium hydride (27 mg, 0.40 mmol) and2,2,2-trifluoroethyl trichloromethanesulfonate (0.140 mL, 0.85 mmol)were added. After 2 h, the reaction was quenched with water and themixture was extracted with ethyl acetate. The organic layer was washedwith water (3×), saturated brine, dried over magnesium sulfate, filteredand concentrated. Purification by silica gel chromatography (0% ethylacetate/hexanes→30% ethyl acetate/hexanes) gave the title compound (306mg). MS 423 (M+1).

Step B:(3R,6S)-3-Amino-6-(2,3-difluorophenyl)-1-(2,2,2-trifluorpethyl)azepan-2-one

Trifluoroacetic acid (2.5 mL) was added to a solution of tert-butyl(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-ylcarbamate(135 mg, 0.320 mmol) in dichloromethane (5 mL). After 30 min, thesolution was concentrated and azeotroped with toluene (2×). Saturatedaqueous sodium bicarbonate solution was added and the mixture wasextracted with dichloromethane (3×). The combined organic extracts werewashed with saturated brine, dried over magnesium sulfate, filtered andconcentrated. MS 323.1 (M+1). ¹H NMR (500 MHz, CDCl₃) δ 7.11-7.03 (m,2H), 6.93-6.89 (m, 1H), 4.21-4.13 (m, 1H), 4.10-3.98 (m, 2H), 3.85 (d,J=11.0 Hz, 1H), 3.35 (d, J=15.4 Hz, 1H), 3.04-2.99 (m, 1H), 2.13-2.09(m, 2H), 2.08-2.02 (m, 1H), 1.78-1.70 (m, 3H).

(3R,6S)-3-Amino-6-(2,3-difluorophenyl)-1-(pyridin-2-ylmethyl)azepan-2-one

Step A. tert-Butyl(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(pyridin-2-ylmethyl)azepan-3-ylcarbamate

Sodium hydride (60% dispersion in mineral oil; 30 mg, 1.175 mmol) wasadded to a solution of tert-butyl(3R,6S)-6-(2,3-difluorophenyl)-2-oxoazepan-3-ylcarbamate (160 mg, 0.470mmol) in N,N-dimethylformamide (6 mL) at 0° C. After 30 min,2-bromomethyl pyridine (0.125 mg, 0.494 mmol) was added. After 1 h, thereaction was quenched with water and the mixture was extracted withethyl acetate. The organic layer was washed with water (2×), saturatedbrine, dried over magnesium sulfate, filtered and concentrated to givethe title compound (202 mg). MS 432.2 (M+1).

Step B.(3R,6S)-3-Amino-6-(2,3-difluorophenyl)-1-(pyridin-2-ylmethyl)azepan-2-on

Trifluoroacetic acid (3 mL) was added to a solution of tert-butyl(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(pyridin-2-ylmethyl)azepan-3-ylcarbamate(202 mg, 0.468 mmol) in dichloromethane (4 mL). After 18 h, the solutionwas concentrated. Saturated aqueous sodium bicarbonate solution wasadded and the mixture was extracted with dichloromethane (3×). Thecombined organic extracts were washed with saturated brine, dried overmagnesium sulfate, filtered and concentrated. MS 332.2 (M+1).

(3R,6S)-3-Amino-6-(2,3-difluorophenyl)-1-pyridin-4-ylazepan-2-one

Step A. tert-Butyl(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-pyridin-4-ylazepan-3-ylcarbamate

4-Bromopyridine (286 mg, 1.47 mmol) was added to a solution oftert-butyl (3R,6S)-6-(2,3-difluorophenyl)-2-oxoazepan-3-ylcarbamate (200mg, 0.588 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (20 mg,0.035 mmol), tris(dibenzylideneacetone)dipalladium(0) (22 mg, 0.024mmol), and cesium carbonate (268 mg, 0.823 mmol) in dioxane (6 mL) andthe mixture was heated at 150° C. in a Personal Chemistry Smith Creator™microwave reactor. After 30 min, an additional amount of4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (20 mg, 0.035 mmol) andtris(dibenzylideneacetone)dipalladium(0) (22 mg, 0.024 mmol) were added.After 30 min, the mixture was partitioned between ethyl acetate andwater. The organic layer was washed with water (2×), saturated brine,dried over magnesium sulfate, filtered and concentrated to give thetitle compound (55 mg). MS 418.2 (M+1).

Step B.(3R,6S)-3-Amino-6-(2,3-difluorophenyl)-1-pylridin-4-ylazepan-2-one

Trifluoroacetic acid (2 mL) was added to a solution of tert-butyl(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-pyridin-4-ylazepan-3-ylcarbamate(55 mg, 0.132 mmol) in dichloromethane (2 mL). After 1 h, the solutionwas concentrated. Saturated aqueous sodium bicarbonate solution wasadded and the mixture was extracted with dichloromethane (3×). Thecombined organic extracts were washed with saturated brine, dried overmagnesium sulfate, filtered and concentrated. MS 318.2 (M+1).

Essentially following the procedures outlined for the preparation ofIntermediates 69-75, the Intermediates in Table 1-4 were prepared. TABLEI-4

Intermediate R MS (M+1) 76 CH₃ 255.2 77 CH₂CH₃ 269.2 78

295.2 79 CH₂CH₂F 287 80 CH₂CHF₂ 305.1 81

325.2 82

325.2 83 CH₂CO₂CH₃ 313.1 84

317.2 85

318.1 86

395.1 87

395.1 88

362.2 89

332 90

332 91

327 92

313 93

325 94

353 95

348 96

338 97

354 98

312 99 CH₂CO₂CH(CH₃)₂ 341 100

418.2 101

352 102

432 103

367 104 CH₂CH₂CF₃ 337 105

341 106

333

(3R,6S)-3-Amino-6-(2,3-difluorophenyl)-1-(2-hydroxy-2-methylpropyl)azepan-2-one

Step A.Di-tert-butyl[(3R,6S)-6-(2,3-difluorophenyl)-1-(2-hydroxy-2-methylpropyl)-2-oxoazepan-3-yl]imidodicarbonate

A solution of(5S)-N²,N²-bis(tert-butoxycarbonyl)-5-(2,3-difluorophenyl)-D-lysine(0.569 g, 1.24 mmol), 1-chloro-2-methyl-2-propanol (0.202 g, 1.86 mmol)and diisopropylethylamine (0.529 g, 4.10 mmol) in EtOH (5 mL) was heatedat 75° C. overnight. The reaction was concentrated to dryness, dilutedwith DCM (20 mL) and EDC (0.358 g, 1.87 mmol), HOAT (0.252 g, 1.87 mmol)were added followed by diisopropylethylamine (0.650 mL, 3.73 mmol).After stirring overnight, NaHCO₃ was added, the layers separated and theaqueous phase backwashed with DCM. The combined organics were dried overmagnesium sulfate, filtered, concentrated and the residue purified bysilica gel chromatography (10%→35% EtOAc/hexanes) to give the titlecompound (0.21 g). MS 513.1 (M+1). ¹H NMR (500 MHz, CD₃OD) δ 7.1 (m,3H), 5.24 (d, J=10.7 Hz, 1H), 4.02 (m, 1H), 3.69 (d, J=13.9 Hz, 1H),3.60 (d, J=15.1 Hz, 1H), 3.39 (m, 1H), 3.24 (d, J=14.2 Hz, 1H), 2.4 (m,1H), 2.1 (m, 3H), 1.5 (s, 18H), 1.20 (s, 3H), 1.16 (s, 3H).

Step B.(3R,6S)-3-Amino-6-(2,3-difluorophenyl)-1-(2-hydroxy-2-methylpropyl)azepan-2-one

A solution ofdi-tert-butyl[(3R,6S)-6-(2,3-difluorophenyl)-1-(2-hydroxy-2-methylpropyl)-2-oxoazepan-3-yl]imidodicarbonate(0.095 g, 0.185 mmol) in DCM (10 mL) was treated with trifluoroaceticacid (3 mL). After 1 h the reaction was concentrated to dryness toafford the title compound as a TFA salt. MS 313.2 (M+1).

(3R,6S)-3-Amino-6-(2,3-difluorophenyl)-1-(1,3-thiazol-2-ylmethyl)azepan-2-one

Step A.Di-tert-butyl[(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(1,3-thiazol-2-ylmethyl)azepan-3-yl]imidodicarbonate

A solution of(5S)-N²,N²-bis(tert-butoxycarbonyl)-5-(2,3-difluorophenyl)-D-lysine(0.871 g, 1.90 mmol), 2-formylthiazole (0.183 g, 1.62 mmol) and aceticacid (0.137 g, 2.28 mmol) in 1,2-dichloroethane (20 mL) was stirred atroom temperature for 30 min. Sodium triacetoxyborohydride (0.604 g, 2.85mmol) was added and the reaction stirred overnight. The reaction wasdiluted with saturated aqueous sodium bicarbonate, the layers separated,and the aqueous phase extracted with DCM (2×). The organic washes werecombined, dried over magnesium sulfate, and concentrated. This residuewas diluted with dichloromethane (20 mL) and EDC (0.569 g, 2.97 mmol),HOAT (0.401 g, 2.97 mmol) were added followed by diisopropylethylamine(1.04 mL, 5.94 mmol). After stirring overnight, NaHCO₃ was added, thelayers separated and the aqueous phase backwashed with DCM. The combinedorganics were dried over magnesium sulfate, filtered, concentrated andthe residue purified by silica gel chromatography (0%→40% EtOAc/hexanes)to give the title compound (0.49 g). MS 538.0 (M+1).). ¹H NMR (500 MHz,CDCl₃) δ 7.73 (d, J=3.5 Hz, 1H), 7.37 (d, J=3.4 Hz, 1H), 7.0 (m, 2H),6.8 (m, 1H), 5.20 (d, J=10.3 Hz, 1H), 5.03 (d, J=15.5 Hz, 1H), 4.96 (d,J=15.5 Hz, 1H), 3.84 (dd, J=10.3, 15.2 Hz, 1H), 3.48 (d, J=15.5 Hz, 1H),2.94 (dd, J=11.0, 11.0 Hz, 1H), 2.50 (dd, 1H), 2.0 (m, 4H), 1.5 (s,18H).

Step B.(3R,6S)-3-Amino-6-(2,3-difluorophenyl)-1-(1,3-thiazol-2-ylmethyl)azepan-2-one

A solution ofdi-tert-butyl[(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(1,3-thiazol-2-ylmethyl)azepan-3-yl]imidodicarbonate(0.481 g, 0.895 mmol) in DCM (10 mL) was treated with trifluoroaceticacid (3 mL). After 1 h the reaction was diluted with saturated aqueoussodium bicarbonate, the layers separated, and the aqueous phaseextracted with DCM (2×). The organic washes were combined, dried overmagnesium sulfate, and concentrated to afford the title compound (0.30mg). MS 338.2 (M+1).

Essentially following the procedures outlined for the preparation ofIntermediates 107-108, the Intermediates in Table 1-5 were prepared.TABLE I-5

Intermediate R MS (M+1) 109 CH(CH₃)₂ 283.2 110 CH₂CH₂OH 285.2 111

322.2 112

335.2 113

335.2 114

335.2 115

352.2 116

325 117

444 118

311 119

313.2 120

366 121

406 122

458 123

350 124

338 125

353.2 126

369.1 (M+H₂O) 127

299.2 128

367.2

Example 1

N-[(3R,6S)-1-(2-Methoxyethyl)-2-oxo-6-phenilazepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide

Triethylamine (0.015 mL, 0.107 mmol) was added to a solution of(3R,6S)-3-amino-1-(2-methoxyethyl)-6-phenylazepan-2-one (28 mg, 0.107mmol) and 4-nitrophenyl chloroformate (22 mg, 0.107 mmol) intetrahydrofuran (2 mL) at 0° C. After 30 min,2-oxo-1-(4-piperidinyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridinedihydrochloride (37 mg, 0.128 mmol), diisopropylethylamine (0.074 mL,0.427 mmol) and dichloromethane (2.5 mL) were added and the mixtureallowed to warm to ambient temperature. After 18 h, saturated aqueoussodium carbonate was added and the mixture was extracted with ethylacetate. The organic layer was washed with saturated aqueous sodiumcarbonate (3×), saturated brine, dried over magnesium sulfate, filteredand concentrated. Purification by silica gel chromatography (100%dichloromethane→93% dichloromethane/methanol) gave the title compound(45 mg). MS 507.2737 (M+1).

Essentially following the procedures outlined for the preparation ofExample 1, the Examples in Table E-1 were prepared. TABLE E-1

Examples C-3 C-6 R¹ MS (M+1) 2 R S H 449 3 R R H 449 4 R S CH₃ 463 5 R SCH₂CH₃ 477 6 R S CH₂CF₃ 531.2326 7 R S CH₂CO₂CH₃ 521.2481 8 R S CH₂CO₂H507.2353 9 R S (CH₂)₂OCH₂CH₃ 521.2910 10 R S CH₂CN 488.2378 11 R S(CH₂)₂OH 493.2555 12 R S

503 13 R S

535.2666 14 R S CH₂CH₂F 495.2489 15 R S CH₂CHF₂ 513.2401 16 R S CH₂CHCF₂525.2392 17 R S

539.2747 18 R S

540.2715 19 R S

533.2858 20 R S

533.2858 21 R S

492.2712 22 R S

535.3008 23 R S

521.2856 24 R S

523.2440 25 R S

555.2379 26 R S (CH₂)₂OCF₃ 561 27 R S

533.2850 28 R S

507.2703 29 R S

521.2867 30 R S

506.2395 31 R s

561.2395 32 R S

533.2821 33 R S Ph 525.2569 34 R S

534.2791

Example 35

N-[(3R)-6-(4-Hydroxyphenyl)-2-oxoazepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide

Triethylamine (0.009 mL, 0.091 mmol) was added to a solution of(3R)-3-amino-6-(4-hydroxyphenyl)azepan-2-one (10 mg, 0.045 mmol) and4-nitrophenyl chloroformate (18 mg, 0.091 mmol) in N,N-dimethylformamide(0.2 mL) and tetrahydrofuran (0.2 mL) at 0° C. After 1 h,2-oxo-1-(4-piperidinyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridinedihydrochloride (26 mg, 0.091 mmol) and diisopropylethylamine (0.032 mL,0.182 mmol) were added and the mixture was allowed to warm to ambienttemperature. After 18 h, the mixture was purified by reverse phase HPLC(C-18, 95% water/acetonitrile→5% water/acetonitrile with 0.1%trifluoroacetic acid) to give the title compound (7 mg). MS 465.2243(M+1).

Essentially following the procedures outlined for the preparation ofExamples 1-35, the Examples in Table E-2 were prepared. TABLE E-2

Examples C-6 R¹ R² MS (M+1) 36 R or S H

467.2189 37 S H

467.2200 38 R or S H

467.2201 39 R or S H

467.2203 40 R or S H

485.2076 41 R H

485.2090 42 R or S H

450 43 R or S H

450.2241 44 R or S H

450.2262 45 R or S

519 46 S

519 47 S

493 48 R

493 49 R or S H

485.2123 50 R or S H

485.2118 51 R or S H

517.2165 52 R or S H

463.2428 53 R or S H

463.2431 54 R or S H

463.2434 55 R or S H

483.1894 56 S H

483.1907 57 R or S H

483.1907 58 R or S H

415.2457 59 R or S H

517.1516 60 R or S H

455.2774 61 R or S H

463.2480 62 R or S H

501.1808 63 S Et

495.2532 64 S CH₂CH₂F

513.2418 65 S CH₂CH₂OMe

525.2629 66 R or S Et

491.2777 67 R or S Me

531.2 68 S Me

531.2 69 S Et

545.2 70 R or S Et

529.2123 71 R or S CH₂CF₃

599.1538

Example 72

N-[(3R)-1-(Cyclopropylmethyl)-2-oxo-6-phenyl-2,3,4,7-tetrahydro-1H-azepin-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-ylpiperidine-1-carboxamide

The title compound was prepared using similar procedures to Examples1-35. MS 501 (M+1).

Example 73

N-[(3R)-1-(Cyclopropylmethyl)-2-oxo-6-pyridin-4-yl-2,3,4,7-tetrahydro-1H-azepin-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide

The title compound was prepared using similar procedures to Examples1-35. MS 502 (M+1).

Example 74

N-[(2S,6R)-4-(Cyclopropylmethyl)-5-oxo-2-phenyl-1,4-oxazepan-6-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide

Triethylamine (0.015 mL, 0.109 mmol) was added to a solution of(2S,6R)-6-amino-4-(cyclopropylmethyl)-2-phenyl-1,4-oxazepan-5-one (27mg, 0.104 mmol) and 4-nitrophenyl chloroformate (22 mg, 0.109 mmol) intetrahydrofuran (2 mL) at 0° C. After 0.5 h, diisopropylethylamine(0.072 mL, 0.415 mmol),2-oxo-1-(4-piperidinyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridinedihydrochloride (36 mg, 0.124 mmol), and dichloromethane (2.5 mL) wereadded and the mixture warmed to ambient temperature. After 18 h, themixture was concentrated. Purification by silca gel chromatography (100%dichloromethane→95% dichloromethane/methanol) gave the title compound(45 mg). MS 505.2559 (M+1).

Example 75

N-[(2S,6R)-2-(2,3-difluorophenyl)-5-oxo-4-(2,2,2-trifluoroethyl)-1,4-oxazepan-6-yl-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide

The title compound was prepared with using a similar procedure toExample 74. MS 569.1943 (M+1).

Example 76

trans-1-(1-{[1-(2-Methoxyethyl)-2-oxo-6-phenylazepan-3-yl]acetyl}piperidin-4-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-4-iumtrifluoroacetate

Step A. Trans-[1-(2-methoxyethyl)-2-oxo-6-phenylazepan-3-yl]acetic acid

Trifluoroacetic acid (1 mL) was added to a solution(trans)-tert-butyl[1-(2-methoxyethyl)-2-oxo-6-phenylazepan-3-yl]acetate(170 mg, 0.47 mmol) in dichloromethane (3 mL). After 2 h, the solutionwas concentrated. MS 306 (M+1).

Step B.trans-1-(1-{[1-(2-Methoxyethyl)-2-oxo-6-phenylazepan-3-yl]acetyl}piperidin-4-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-4-iumtrifluoroacetate

Triethylamine (0.33 mL, 2.35 mmol) was added to a solution oftrans-[1-(2-methoxyethyl)-2-oxo-6-phenylazepan-3-yl]acetic acid (143.6mg, 0.47 mmol),2-oxo-1-(4-piperidinyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridinedihydrochloride (136 mg, 0.47 mmol),1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (180 mg,0.941 mmol), and 1-hydroxybenzotriazole hydrate (72 mg, 0.47 mmol) inN,N-dimethylformamide (4 mL). After 18 h, the reaction was concentrated.Purification by reverse phase HPLC (C-18, 95% water/acetonitrile→5%water/acetonitrile with 0.1% trifluoroacetic acid) gave the titlecompound (187 mg). MS 506 (M+1).

Example 77

1-(2-Methoxyethyl)-2-oxo-6-phenylazepan-3-yl]acetyl}piperidin-4-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-4-iumtrifluoroacetate

The title compound was prepared with(cis)-tert-butyl[1-(2-methoxyethyl)-2-oxo-6-phenylazepan-3-yl]acetateusing a similar procedure to Example 76. MS 506 (M+1).

Essentially following the procedures outlined for the preparation ofExample 76, the Examples in Table E-3 were prepared. TABLE E-3

Examples C-3 C-6 R¹ MS (M+1) 78 R S

502.2813 79 S R

502 80 R R

502 81 S S

502

Example 82

N-{(3R,6S)-6-(2,3-Difluorophenyl)-1-[2-(methylthio)ethyl]-2-oxoazepan-3-yl}-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide

Triethylamine (0.020 mL, 0.143 mmol) was added to a solution of(3R,6S)-3-amino-6-(2,3-difluorophenyl)-1-[2-(methylthio)ethyl]azepan-2-one(45 mg, 0.143 mmol) and 4-nitrophenyl chloroformate (29 mg, 0.143 mmol)in tetrahydrofuran (3 mL) at 0° C. After 15 min,2-oxo-1-(4-piperidinyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridinedihydrochloride (46 mg, 0.157 mmol), triethylamine (0.080 mL, 0.572mmol) and dichloromethane (5 mL) were added and the mixture was heatedto 50° C. After 30 min, the mixture was allowed to cool to ambienttemperature and concentrated. Purification by silica gel chromatography[100% dichloromethane→95% dichloromethane/methanol (10% ammoniumhydroxide/methanol)] gave the title compound (60 mg). The title compoundwas converted to the HCl salt with 2M HCl in ether. MS 559.2 (M+1). ¹HNMR (500 MHz, CD₃OD) δ 8.11 (dd, J=7.8 Hz, 1.0 Hz, 1H), 7.99 (dd, J=6.1Hz, 1.0 Hz, 1H), 7.38-7.35 (m, 1H), 7.18-7.14 (m, 3H), 4.76 (d, J=10.7Hz, 1H), 4.61-4.54 (m, 1H), 4.31-4.26 (m, 2H), 4.15-4.09 (m, 1H),3.85-3.80 (m, 1H), 3.67-3.58 (m, 1H), 3.37 (d, J=15.4 Hz, 1H), 3.20-3.16(m, 1H), 3.08-2.96 (m, 2H), 2.75-2.70 (m, 2H), 2.49-2.41 (m, 1H),2.34-2.26 (m, 1H), 2.21-2.16 (m, 1H), 2.14 (s, 3H), 2.11-2.07 (m, 2H),1.90-1.85 (m, 3H).

Example 83

N-{(3R,6S)-6-(2,3-Difluorophenyl)-1-[2-(methylsulfinyl)ethyl]-2-oxoazepan-3-yl}-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide

Triethylamine (0.010 mL, 0.027 mmol) was added to a solution of(3R,6S)-3-amino-6-(2,3-difluorophenyl)-1-[2-(methylsulfinyl)ethyl]azepan-2-one(8.9 mg, 0.027 mmol) and 4-nitrophenyl chloroformate (5.4 mg, 0.027mmol) in tetrahydrofuran (0.700 mL) at 0° C. After 45 min,2-oxo-1-(4-piperidinyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridinedihydrochloride (7.9 mg, 0.027 mmol) and triethylamine (0.040 mL, 0.108mmol) were added and the mixture allowed to warm to ambient temperature.After 16 h, the mixture was concentrated. Purification by reverse phaseHPLC (C-18, 95% water/acetonitrile→5% water/acetonitrile with 0.1%trifluoroacetic acid) gave the title compound. MS 575 (M+1).

Example 84

N-{(3R,6S)-6-(2,3-Difluorophenyl)-1-[2-(methylsulfonyl)ethyl]-2-oxoazepan-3-yl}-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide

Triethylamine (0.010 mL, 0.023 mmol) was added to a solution of(3R,6S)-3-amino-6-(2,3-difluorophenyl)-1-[2-(methylsulfonyl)ethyl]azepan-2-one(8 mg, 0.023 mmol) and 4-nitrophenyl chloroformate (4.6 mg, 0.023 mmol)in tetrahydrofuran (0.700 mL) at 0° C. After min,2-oxo-1-(4-piperidinyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridinedihydrochloride (6.7 mg, 0.023 mmol) and triethylamine (0.040 mL, 0.092mmol) were added and the mixture allowed to warm to ambient temperature.After 16 h, the mixture was concentrated. Purification by reverse phaseHPLC (C-18, 95% water/acetonitrile>5% water/acetonitrile with 0.1%trifluoroacetic acid) gave the title compound. MS 591 (M+1).

Example 85

N-[(3R,6S)-6-(2,3-Difluorophenyl)-1-(2-methoxyethyl)-2-oxoazepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide

Triethylamine (0.030 mL, 0.218 mmol) was added to a solution of(3R,6S)-3-amino-6-(2,3-difluorophenyl)-1-(2-methoxyethyl)azepan-2-one(65 mg, 0.218 mmol) and 4-nitrophenyl chloroformate (44 mg, 0.218 mmol)in tetrahydrofuran (3 mL) at 0° C. After 30 min,2-oxo-1-(4-piperidinyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridinedihydrochloride (70 mg, 0.240 mmol), triethylamine (0.120 mL, 0.872mmol), and dichloromethane (5 mL) were added and the mixture allowed towarm to ambient temperature. After 4.5 h, the mixture was concentrated.Purification by silica gel chromatography [100% dichloromethane→95%dichloromethane/methanol (10% ammonium hydroxide/methanol)] gave thetitle compound (88 mg). The title compound was converted to the HCl saltwith 2M HCl in ether. MS 543.3 (M+1). ¹H NMR (500 MHz, CD₃OD) δ 8.09(dd, J=7.8 Hz, 1.0 Hz, 1H), 7.99 (dd, J=6.1 Hz, 1.0 Hz, 1H), 7.36(m,1H), 7.17-7.10 (m, 3H), 4.78 (d, J=11.0 Hz, 1H), 4.61-4.54 (m, 1H),4.31-4.24 (m, 2H), 4.18-4.13 (m, 1H), 3.94-3.89 (m, 1H), 3.57-3.53 (m,2H), 3.48-3.43 (m, 1H), 3.39 (d, J=15.1 Hz, 1H), 3.34 (s, 3H), 3.19-3.15(m, 1H), 3.07-2.96 (m, 2H), 2.49-2.41 (m, 1H), 2.35-2.26 (m, 1H),2.19-2.06 (m, 3H), 1.90-1.76 (m, 3H).

Example 86

N-[(3R,6S)-6-(2,3-Difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide

Triethylamine (0.038 mL, 0.276 mmol) was added to a solution of(3R,6S)-3-amino-6-(2,3-difluorophenyl)-1-(2,2,2-trifluoroethyl)azepan-2-one(89 mg, 0.276 mmol) and 4-nitrophenyl chloroformate (56 mg, 0.276 mmol)in tetrahydrofuran (3 mL) at 0° C. After 30 min,2-oxo-1-(4-piperidinyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridinedihydrochloride (88 mg, 0.304 mmol), triethylamine (0.152 mL, 1.104mmol), and dichloromethane (5 mL) were added and the mixture allowed towarm to ambient temperature. After 48 h, the mixture was concentrated.Purification by silica gel chromatography [100% dichloromethane→95%dichloromethane/methanol (10% ammonium hydroxide/methanol)] gave thetitle compound (98 mg). The title compound was converted to the HCl saltwith 2M HCl in ether. MS 567.2 (M+1). ¹H NMR (500 MHz, CD₃OD) δ 8.11(dd, J=7.8 Hz, 1.0 Hz, 1H), 8.00 (dd, J=5.9 Hz, 1.0 Hz, 1H), 7.34-7.31(m, 1H), 7.19-7.13 (m, 3H), 4.86-4.83 (m, 1H), 4.62-4.57 (m, 1H),4.49-4.41 (m, 1H), 4.33-4.25 (m, 3H), 4.12-4.04 (m, 1H), 3.51-3.46 (m,1H), 3.18-3.14 (m, 1H), 3.09-2.96 (m, 2H), 2.51-2.44 (m, 1H), 2.33-2.25(m, 1H), 2.22-2.10 (m, 3H), 1.90-1.81 (m, 3H).

Example 87

N-[(3R,6S)-6-(2,3-Difluorophenyl)-2-oxo-1-(pyridin-2-ylmethyl)azepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide

Triethylamine (0.065 mL, 0.468 mmol) was added to a solution of(3R,6S)-3-amino-6-(2,3-difluorophenyl)-1-(pyridin-2-ylmethyl)azepan-2-one(180 mg, 0.417 mmol) and 4-nitrophenyl chloroformate (94 mg, 0.468 mmol)in tetrahydrofuran (3 mL) at 0° C. After 1 h,2-oxo-1-(4-piperidinyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridinedihydrochloride (136 mg, 0.468 mmol) and triethylamine (0.195 mL, 1.404mmol) were added and the mixture allowed to warm to ambient temperature.After 18 h, the mixture was partitioned between ethyl acetate and water.The organic layer was washed with water (2×), saturated brine, driedover magnesium sulfate, filtered and concentrated. Purification bysilica gel chromatography [100% dichloromethane→95%dichloromethane/methanol (10% ammonium hydroxide/methanol)] gave thetitle compound (240 mg). The title compound was converted to the HClsalt with 2M HCl in ether. MS 576.3 (M+1). ¹H NMR (500 MHz, CD₃OD) δ8.78 (d, J=5.9 Hz, 1H), 8.62-8.59 (m, 1H), 8.07 (d, J=8.3 Hz, 1H),8.03-7.98 (m, 3H), 7.32 (dd, J=8.1 Hz, 6.1, 1H), 7.18-7.15 (m, 3H), 5.43(d, J=16.9 Hz, 1H), 4.75 (d, J=17.1 Hz, 1H), 4.56-4.51 (m, 1H),4.36-4.28 (m, 3H), 3.51 (d, J=15.1 Hz, 1H), 3.48 (s, 1H), 3.22-3.17 (m,1H), 3.05-2.98 (m, 2H), 2.44-2.40 (m, 1H), 2.34-2.23 (m, 2H), 2.18-2.14(m, 2H), 1.97-1.92 (m, 1H), 1.89-1.88 (m, 2H).

Example 88

N-[(3R,6S)-6-(2,3-Difluorophenyl)-2-oxo-1-pyridin-4-ylazepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide

Triethylamine (0.018 mL, 0.132 mmol) was added to a solutionof(3R,6S)-3-amino-6-(2,3-difluorophenyl)-1-pyridin-4-ylazepan-2-one (42mg, 0.132 mmol) and 4-nitrophenyl chloroformate (27 mg, 0.132 mmol) intetrahydrofuran (2 mL) at 0° C. After 1 h,2-oxo-1-(4-piperidinyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridinedihydrochloride (38 mg, 0.132 mmol) and triethylamine (0.054 mL, 0.396mmol) were added and the mixture allowed to warm to ambient temperature.After 18 h, the mixture was partitioned between ethyl acetate and water.The organic layer was washed with water (2×), saturated brine, driedover magnesium sulfate, filtered and concentrated. Purification bysilica gel chromatography [100% dichloromethane→95%dichloromethane/methanol (10% ammonium hydroxide/methanol)] gave thetitle compound (53 mg). The title compound was converted to the HCl saltwith 2M HCl in ether. MS 562.2 (M+1). ¹H NMR (500 MHz, CD₃OD) δ 8.76 (d,J=7.6 Hz, 2H), 8.11 (d, J=7.3 Hz, 2H), 8.00 (d, J=6.4 Hz, 2H), 7.30 (t,J=7.0 Hz, 1H), 7.27-7.21 (m, 3H), 5.11 (d, J=11.5 Hz, 1H), 4.72-4.65 (m,1H), 4.60-4.55 (m, 1H), 4.35-4.33 (m, 2H), 4.14 (d, J=16.1 Hz, 1H),3.42-3.39 (m, 1H), 3.09-3.02 (m, 2H), 2.47-2.44 (m, 1H), 2.37-2.30 (m,2H), 2.24-2.18 (m, 2H), 2.06-2.03 (m, 1H), 1.91 (br. s, 2H).

Example 89

N-[(3R,6S)-6-(2,3-Difluorophenyl)-2-oxo-1-(1,3-thiazol-2-ylmethyl)azepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide

Triethylamine (0.156 mL, 0.1.12 mmol) was added to a solution of(3R,6S)-3-amino-6-(2,3-difluorophenyl)-1-(1,3-thiazol-2-ylmethyl)azepan-2-one(302 mg, 0.895 mmol) and 4-nitrophenyl chloroformate (217 mg, 1.074mmol) in tetrahydrofuran (15 mL) at 0° C. After 30 min,2-oxo-1-(4-piperidinyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridinedihydrochloride (782 mg, 2.685 mmol), triethylamine (5.37 mmol) anddichloromethane (15 mL) were added and the mixture allowed to warm toambient temperature. The reaction was stirred overnight, concentrated,diluted with saturated aqueous sodium bicarbonate and extracted withdichloromethane (2×). The organic layer was washed with water, saturatedbrine, dried over magnesium sulfate, filtered and concentrated.Purification by silica gel chromatography (0%→8%methanol/dichloromethane) gave the title compound (400 mg). MS 582.2109(M+1). ¹H NMR (500 MHz, CDCl₃) δ 8.06 (d, J=4.5 Hz, 1H), 7.73 (d, J=3.4Hz, 1H), 7.35 (m, 2H), 7.0 (m, 2H), 6.98 (dd, J=5.4, 7.8 Hz, 1H), 6.85(m, 1H), 6.21 (d, J=5.3 Hz, 1H), 5.0 (app q, J=15 Hz, 2H), 4.85 (dd,J=5.0, 11.1 Hz, 1H), 4.58 (m, 1H), 4.27 (br dd, 2H), 4.00 (dd, J=10.6,15.1 Hz, 1H), 3.50 (d, J=15.1 Hz, 1H), 3.0 (br dd, 1h), 2.88 (dd,J=10.0, 10.0 Hz, 1H), 2.2-1.6 (m, 8H).

Example 90

N-[(3R,6S)-6-(2,3-difluorophenyl)-1-(2-hydroxy-2-methylpropyl)-2-oxoazepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide

Triethylamine (0.054 mL, 0.389 mmol) was added to a solution of(3R,6S)-3-amino-6-(2,3-difluorophenyl)-1-(2-hydroxy-2-methylpropyl)azepan-2-one(54 mg, 0.173 mmol) and 4-nitrophenyl chloroformate (40 mg, 0.199 mmol)in tetrahydrofuran (15 mL) at 0° C. After min,2-oxo-1-(4-piperidinyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridinedihydrochloride (151 mg, 0.519 mmol), triethylamine (1.04 mmol) andchloroform (15 mL) were added and the mixture allowed to warm to ambienttemperature. The reaction was then heated to 50° C. for 2 h,concentrated, diluted with saturated aqueous sodium bicarbonate andextracted with dichloromethane (2×). The organic layer was washed withwater, saturated brine, dried over magnesium sulfate, filtered andconcentrated. Purification by silica gel chromatography (1.5%→11%methanol/dichloromethane) gave the title compound (70 mg). MS 557.2653(M+1). ¹H NMR (500 MHz, CDCl₃) δ 8.03 (d, J=4.8 Hz, 1H), 7.34 (d, J=7.7Hz, 1H), 7.1 (m, 2H), 7.0-6.9 (m, 2H), 6.17 (d, J=5.1 Hz, 1H), 4.84 (dd,J=10.9, 5.0 Hz, 1H), 4.5 (m, 1H), 4.3 (br dd, 2H), 4.02 (dd, J=10.1,15.1 Hz, 1H), 3.76 (d, J=14.1 Hz, 1H), 3.42 (d, J=15.1 Hz, 1H), 3.31 (d,J=14.1 Hz, 1H), 3.15-2.95 (m, 4H), 2.3-1.9 (m, 8H), 1.26 (s, 3H), 1.24(s, 3H).

Essentially following the procedures outlined for the preparation ofExamples 82-90, the Examples in Table E-4 were prepared. TABLE E-4

Example R MS (M+1) 91 CH₃ 499.2 92 CH₂CH₃ 513.2 93

539.3 94 CH₂CH₂F 531.1 95 CH₂CHF₂ 549.1 96

569.3 97

569.3 98 CH₂CO₂CH₃ 557.2287 99

561.2 100

562.2 101

639.2 102

639.2 103

606.3 104

566.2344 105 CH(CH₃)₂ 527.2545 106

579.2658 107

579.2656 108

579.2657 109

596.2242 110

576.2496 111

576.2499 112

571 113

557.2 114

569.2651 115

597.2193 116 CH₂CO₂H 543.2163 117

592.2433 118 CH₂CH₂SO₂CH₃ 591.2169 119

582.2972 120

598.2944 121

556.2834 122 CH₂CO₂CH(CH₃)₂ 585 123

528.3 124

596.2681 125

596.3153 126

554.2665 127

555.2526 128

542.2683 129

611.3289 130

557.2666 131 CH₂CH₂CF₃ 581.2296 132

585.2655 133

571 134

577.2484 135

610.2954 136

650.2914 137

568.2834 138

594.2412 139

582.2901 140 CH₂CH₂OH 529.2383 141

597.2244 142

595.2064 143

543.2504 144

612.3378 145

541.2362

Example 146

N-[(3R,6S)-6-(2,3-Difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl]-4-(8-oxo-8,9-dihydro-7H-purin-7-yl)piperidine-1-carboxamide

Triethylamine (0.030 mL, 0.215 mmol) was added to a solution of(3R,6S)-3-amino-6-(2,3-difluorophenyl)-1-(2,2,2-trifluoroethyl)azepan-2-one(80 mg, 0.248 mmol) and 4-nitrophenyl chloroformate (44 mg, 0.218 mmol)in tetrahydrofuran (3 mL) at 0° C. After 0.5 h,7-piperidin-4-yl-7,9-dihydro-8H-purin-8-one hydrochloride (73 mg, 0.248mmol) and triethylamine (0.120 mL, 0.860 mmol) were added and themixture allowed to warm to ambient temperature. After 18 h, the mixturewas partitioned between ethyl acetate and water. The organic layer waswashed with water (2×), saturated brine, dried over magnesium sulfate,filtered and concentrated. Purification by silica gel chromatography(100% dichloromethane→95% dichloromethane/methanol) gave the titlecompound (114 mg). MS 567.2123 (M+1).

Essentially following the procedures outlined for the preparation ofExample 146, the Examples in Table E-5 were prepared. TABLE E-5

Example R MS (M + 1) 147 CH₃ 500.2182 148

540.2493 149 CH₂CHF₂ 550.2159 150 CH₂CH₂OCF₃ 598.2147 151 CH₂CH₂SCH₃560.2217 152 CH₂CH₂SOCH₃ 576.2174 153 CH₂CH₂SO₂CH₃ 592.2 154 CH₂CH₂OCH₃544.2473 155 CH₂CH₂OH 530.2336 156

562.2338 157

612.2349

Example 158

N-[(3R,6S)-6-Phenyl-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl]-4-(8-oxo-8,9-dihydro-7H-purin-7-yl)piperidine-1-carboxamide

Prepared essentially following the procedure outlined for thepreparation of Example 146. MS 532.2250 (M+1).

Example 159

4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-1-yl)-N-[(3R,6S)-2-oxo-6-phenyl-1-(2,2,2-trifluoroethyl)azepan-3-yl]piperidine-1-carboxamide

Prepared essentially following the procedure outlined for thepreparation of Example 146. MS 532.2292 (M+1).

Example 160

N-[(3R,6S)-6-(2,3-Difluorophenyl)-1-(2-methoxyethyl)-2-oxoazepan-3-yl]-4-(6-oxo-6,7-dihydro-5H-imidazo[4,5-c]pyridazin-5-yl)piperidine-1-carboxamide

Prepared essentially following the procedure outlined for thepreparation of Example 146. MS 544.2465 (M+1).

Example 161

N-[(3R,6S)-6-(2,3-Difluorophenyl)-1-(2-methoxyethyl)-2-oxoazepan-3-yl]-4-(2-oxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-yl)piperidine-1-carboxamide

Prepared essentially following the procedure outlined for thepreparation of Example 146. MS 557.2645

Example 162

N-[(3R,6S)-6-(2,3-Difluorophenyl)-1-(2-methoxyethyl)-2-oxoazepan-3-yl]-4-(2-oxo-1,4-dihydropyido[4,3-d]pyrimidin-3(2H)-yl)piperidine-1-carboxamide

Prepared essentially following the procedure outlined for thepreparation of Example 146 MS 557.2683

Example 163

N-[(3R,6S)-6-(2,3-Difluorophenyl)-1-(2-methoxyethyl)-2-oxoazepan-3-yl]-4-(2-oxo-1,4-dihydropyrido[2,3-d]pyrimidin-3(2H)-yl)piperidine-1-carboxamide

Prepared essentially following the procedure outlined for thepreparation of Example 146. MS 557.2701

Example 164

N-[(3R,6S)-6-(2,3-Difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl]-4-(5-methoxy-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide

Prepared essentially following the procedure outlined for thepreparation of Example 146. MS 597.2228 (M+1).

Example 165

N-[(3R,6S)-6-(2,3-Difluorophenyl)-1-(2-hydroxy-2-methylpropyl)-2-oxoazepan-3-yl]-4-(6-fluoro-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide

Prepared essentially following the procedure outlined for thepreparation of Example 146. MS 575.2584 (M+1).

Example 166

N-[(3R,6S)-6-(2,3-Difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl]-4-(4-oxido-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide

Prepared essentially following the procedure outlined for thepreparation of Example 146. MS 583.2076 (M+1).

Example 167

N-[(3R,6S)-6-(2,3-Difluorophenyl)-1-methyl-2-oxoazepan-3-yl]-4-(4-oxido-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide

Prepared essentially following the procedure outlined for thepreparation of Example 146. MS 515.2205 (M+1).

Example 168

Step A. PhenylN′-cyano-N-[(3R,6S)-6-(2,3-difluorophenyl)-1-ethyl-2-oxoazepan-3-yl]imidocarbamate

A solution of (3R,6S)-3-amino-6-(2,3-difluorophenyl)-1-ethylazepan-2-one(135 mg, 0.503 mmol) in dichloromethane was treatedN,N-diisopropylethylamine (65 mg, 0.503 mmol) and diphenylN-cyanocarbonimidate (204 mg, 0.855 mmol). After 5 h, the reaction wasquenched with 0.5N NaOH and the organic layer washed with water andbrine. The combined aqueous layers were extracted with EtOAc. Thecombined organics were dried, filtered and concentrated. Purification bysilica gel chromatography (EtOAc/hexanes) gave the title compound (166mg). MS 413.3 (M+1).

Step B.N-Cyano-N-[(3R,6S)-6-(2,3-difluorophenyl)-1-ethyl-2-oxoazepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboximidamide

A solution of phenylIV-cyano-N-[(3R,6S)-6-(2,3-difluorophenyl)-1-ethyl-2-oxoazepan-3-yl]imidocarbamate(166 mg, 0.402 mmol) and2-oxo-1-(4-piperidinyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridinedihydrochloride (116 mg, 0.402 mmol), in I-pentanol (10 mL) was treatedwith N,N-diisopropylethylamine (52 mg, 0.402 mmol). This mixture washeated to reflux for 24 h. Concentration and purification by silica gelchromatography (0%→10% methanol/dichloromethane) followed by reversephase HPLC (C-18, 95% water/acetonitrile→5% water/acetonitrile with 0.1%trifluoroacetic acid) gave the title compound (10 mg). MS 537.5 (M+1).

Example 169

N-[(3R,6S)-6-(2,3-Difluorophenyl)-7-(hydroxymethyl)-2-oxoazepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide

Step A. Benzyl(2R,5S)-2-[bis(tert-butoxycarbonyl)amino]-5-(2,3-difluorophenyl)-7-hydroxy-6-nitroheptanoate

To a solution of(5S)-N,N-bis(tert-butoxycarbonyl)-5-(2,3-difluorophenyl)-6-nitro-D-norleucinate(2.30 g, 3.975 mmol) and 1,1,3,3-tetramethylguanidine (46 mg, 0.40 mmol)in acetonitrile (20 mL) was added formaldehyde (0.15 mL, 37% aqueoussolution). After stirring for 60 min, more formaldehyde (0.050 mL, 37%aqueous solution) was added. After stirring for an additional 60 min themixture was diluted with saturated aqueous NaHCO₃ and extracted withCH₂Cl₂ (3×). The combined organics were dried over magnesium sulfate,filtered and concentrated to give a residue that was purified by silicagel chromatography (25%→75% ethyl acetate/hexanes) to give the titlecompound (1.44 g,). MS 409.1 (M+1-2Boc).

Step B.(5S)-N²,N²-bis(tert-Butoxycarbonyl)-5-(2,3-difluorophenyl)-6-(hydroxymethyl)-D-lysine

A solution of benzyl(2R,5S)-2-[bis(tert-butoxycarbonyl)amino]-5-(2,3-difluorophenyl)-7-hydroxy-6-nitroheptanoate(180 mg, 0.49 mmol) and 10% Pd/C (300 mg) in EtOH (5 mL, SureSeal fromAldrich), was hydrogenated at 55 psi for 7 d (200 mg more Pd/C was addedafter 3 d). The reaction was filtered through Celite with more EtOH andconcentrated to afford the title compound (180 mg). MS 489.1 (M+1).

Step C.Di-tert-butyl[(3R,6S)-6-(2,3-difluorophenyl)-7-(hydroxymethyl)-2-oxoazepan-3-yl]imidodicarbonate

To a solution(5S)-N²,N²-bis(tert-butoxycarbonyl)-5-(2,3-difluorophenyl)-6-(hydroxymethyl)-D-lysine(180 mg, 0.37 mmol) in DCM (5 mL) were added EDC (106 mg, 0.55 mmol) andHOAT (50 mg, 0.37 mmol). After 30 min, NaHCO₃ was added, the layersseparated and the aqueous phase backwashed with DCM. The combinedorganics were dried over magnesium sulfate, filtered and concentratedand the residue purified by silica gel chromatography (0%→10% MeOH/DCM)to give the title compound (100 mg). MS 471.1 (M+1).

Step D.(3R,6S)-3-amino-6-(2,3-difluorophenyl)-7-(hydroxymethyl)azepan-2-one

Di-tert-butyl[(3R,6S)-6-(2,3-difluorophenyl)-7-(hydroxymethyl)-2-oxoazepan-3-yl]imidodicarbonate(100 mg, 0.213 mmol) was diluted DCM (30 mL) and TFA (8 mL) was added.After 2 h, the reaction was concentrated to give the title compound asits TFA salt (57 mg). MS 271.0 (M+1).

Step E.N-[(3R,6S)-6-(2,3-difluorophenyl)-7-(hydroxymethyl)-2-oxoazepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide

Triethylamine (0.68 mL, 0.49 mmol) was added to a solution of(3R,6S)-3-amino-6-(2,3-difluorophenyl)-7-(hydroxymethyl)azepan-2-one (57mg, 0.21 mmol) and 4-nitrophenyl chloroformate (47 mg, 0.23 mmol) intetrahydrofuran (10 mL) at 0° C. After 30 min,2-oxo-1-(4-piperidinyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridinedihydrochloride (98 mg, 0.34 mmol), triethylamine (0.84 mmol) andchloroform (10 mL) were added and the mixture allowed to warm to ambienttemperature. The reaction was stirred overnight, concentrated, dilutedwith saturated aqueous sodium bicarbonate and extracted withdichloromethane (2×). The organic layer was washed with water, saturatedbrine, dried over magnesium sulfate, filtered and concentrated.Purification by silica gel chromatography (1%→12%methanol/dichloromethane) gave the title compound (17 mg). MS 515.2203(M+1).

Example 170

N-[5-(2,3-Difluorophenyl)-1-(2-methoxyethyl)-2-oxopiperidin-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide

Step A. 5-Bromo-1-(2-methoxyethyl)-3-nitropyridin-2(1H)-one

Cesium carbonate (14.88 g, 45.66 mmol) was added to a solution of5-bromo-3-nitropyridin-2-ol (10.0 g, 45.7 mmol) and 2-bromoethyl methylether (4.29 mL, 45.66 mmol) in N,N-dimethylformamide (400 mL). After 3h, additional 2-bromoethyl methyl ether (4.29 mL, 45.7 mmol) was added,and the reaction was heated to 60° C. After 4 h, water was added. Themixture was extracted with ethyl acetate (3×), and the combined organicextracts were washed with saturated brine, dried over sodium sulfate,filtered and concentrated. Purification by silica gel chromatography(100% hexanes→40% ethyl acetate/hexanes) gave the title compound (7.39g). MS 277 (M).

Step B.5-(2,3-Difluorophenyl)-1-(2-methoxyethyl)-3-nitropyridin-2(1H)-one

Palladium acetate (41.0 mg, 0.18 mmol) was added to a solution of5-bromo-1-(2-methoxyethyl)-3-nitropyridin-2(1H)-one (500 mg, 1.81 mmol),2,3-difluorophenyl boronic acid (570 mg, 3.61 mmol), diisopropylamine(0.759 mL, 5.41 mmol) and 3,3′,3″-phosphinidynetris(benzenesulfonicacid) trisodium salt (310 mg, 0.541 mmol), in N,N-dimethylformamide (15mL) and water (5 mL) and heated to 80° C. After 2 h, the mixture wasallowed to cool to ambient temperature and filtered. Purification byreverse phase HPLC (C-18, 95% water/acetonitrile→5% water/acetonitrilewith 0.1% trifluoroacetic acid) gave the title compound (335 mg). MS 311(M+1). ¹H NMR (500 MHz, CDCl₃) δ 8.56 (d, J=2.7 Hz, 1H), 8.03 (d, J=2.4Hz, 1H), 7.23-7.18 (m, 2H), 7.15-7.12 (m, 1H), 4.33 (t, J=4.8 Hz, 2H),3.74 (t, J=4.8 Hz, 2H), 3.35 (s, 3H).

Step C. 3-Amino-5-(2,3-difluorophenyl)-1-(2-methoxyethyl)piperidin-2-one

10% Platinum on carbon (320 mg) was added to a solution of5-(2,3-difluorophenyl)-1-(2-methoxyethyl)-3-nitropyridin-2(1H)-one (300mg, 0.967 mmol) in acetic acid (10 mL). The reaction vessel wasevacuated and back-filled with nitrogen (3×), then back-filled withhydrogen (56 psi). After 65 h, the mixture was filtered andconcentrated. MS 285 (M+1).

Step D.N-[5-(2,3-Difluorophenyl)-1-(2-methoxyethyl)-2-oxopiperidin-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide

Triethylamine (83 μL, 0.598 mmol) was added to a solution of3-amino-5-(2,3-difluorophenyl)-1-(2-methoxyethyl)piperidin-2-one (170mg, 0.598 mmol) and 4-nitrophenylchloroformate (121 mg, 0.598 mmol) intetrahydrofuran (4 mL) at 0° C. After 1 h,2-oxo-1-(4-piperidinyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridinedihydrochloride (174 mg, 0.651 mmol), triethylamine (249 μL, 1.794 mmol)were added and the mixture allowed to warm to ambient temperature. After18 h, saturated aqueous sodium bicarbonate was added and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated aqueous sodium bicarbonate (3×), saturated brine, dried oversodium sulfate, filtered and concentrated. Purification by silica gelchromatography [100% dichloromethane→95% dichloromethane/5% (10%ammonium hydroxide/methanol)] gave the title compound (0.135 g). MS529.2353 (M+1). ¹H NMR (500 MHz, CDCl₃) δ 8.03 (dd, J=5.3, 1.1 Hz, 1H),7.38 (dd, J=7.8, 1.2 Hz, 1H), 7.11-7.03 (m, 2H), 7.01-6.96 (m, 2H), 5.82(d, J=3.4 Hz, 1H), 4.58-4.53 (m, 1H), 4.34-4.30 (m, 1H), 4.23 (d, J=6.6Hz, 2H), 3.71-3.62 (m, 3H), 3.60-3.53 (m, 3H), 3.52-3.46 (m, 1H), 3.33(s, 3H), 2.96 (dd, J=23.4, 10.5 Hz, 2H), 2.80-2.78 (m, 1H), 2.28-2.21(m, 2H), 1.90 (dd, J=10.5, 2.0 Hz, 2H).

Essentially following the procedures outlined for the preparation ofExample 170, the Examples in Table E-6 were prepared. TABLE E-6

Examples C-3 C-5 R¹ R² MS (M + 1) 171 R or S R or S CH₂CH₂OCH₃

493.2519 172 R or S R or S CH₃

449.2285 173 R or S R or S CH₃

485.2098 174 R or S R or S CH₂CF₃

517.2154 175 R or S R or S CH₂CF₃

553.1962 176 R R CH₂CF₃

517 177 R S CH₂CF₃

517 178 S R CH₂CF₃

517 179 S S CH₂CF₃

517

Example 180

N-[1-(2,3-Difluorobenzyl)-5-oxo-4-(2,2,2-trifluoroethyl)-1,4-diazepan-6-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide

Step A: Benzyl6-[(tert-butoxycarbonyl)amino]-5-oxo-1,4-diazepane-1-carboxylate

Triethylamine (0.56 mL, 3.99 mmol) was added to a solution of benzyl6-amino-5-oxo-1,4-diazepane-1-carboxylate (1.05 g, 3.99 mmol) anddi-tert-butyl dicarbonate (1.31 g, 6.00 mmol) in dichloromethane (30mL). After 18 h, water was added, and the mixture was extracted withethyl acetate. The organic layer was washed with brine, dried overmagnesium sulfate, filtered and concentrated. Purification by silica gelchromatography (100% dichloromethane→95% dichloromethane/methanol) gavethe title compound (1.35 g). MS 364 (M+1).

Step B: Benzyl6-[(tert-butoxycarbonyl)amino]-5-oxo-4-(2,2,2-trifluoroethyl)-1,4-diazepane-1-carboxylate

Sodium hydride (60% dispersion in mineral oil; 180 mg, 4.43 mmol) wasadded to a solution of benzyl6-[(tert-butoxycarbonyl)amino]-5-oxo-1,4-diazepane-1-carboxylate (1.34g, 3.69 mmol) in N,N-dimethylformamide (25 mL) at −35° C. After 15 min,2,2,2-trifluoroethyl trichloromethanesulfonate (0.911 mL, 5.54 mmol) wasadded and the reaction was stirred at −35° C. After 2 h, an additionalamount of sodium hydride (100 mg, 2.5 mmol) andtrichloromethanesulfonate (0.500 mL, 3.04 mmol) were added. After 18 h,the reaction was quenched with water and the mixture was extracted withethyl acetate. The organic layer was washed with water (3×), saturatedbrine, dried over magnesium sulfate, filtered and concentrated.Purification by silica gel chromatography (hexanes→30% ethylacetate/hexanes) gave the title compound (690 mg). MS 446 (M+1).

Step C: tert-Butyl7-oxo-1-(2,2,2-trifluoroethyl)-1,4-diazepan-6-ylcarbamate

10% Palladium on carbon (77 mg) was added to a solution of benzyl6-[(tert-butoxycarbonyl)amino]-5-oxo-4-(2,2,2-trifluoroethyl)-1,4-diazepane-1-carboxylate(590 mg, 1.32 mmol) in ethanol (20 mL). The reaction vessel wasevacuated and back-filled with nitrogen (3×), then back-filled withhydrogen (1 atm). After 18 h, the mixture was filtered and concentratedto give the title compound (420 mg). MS 312 (M+1). ¹H NMR (500 MHz,CDCl₃) δ 5.83 (s, 1H), 4.53-4.49 (m, 1H), 4.29-4.20 (m, 1H), 3.96-3.88(m, 1H), 3.81-3.77 (m, 1H), 3.38 (d, J=15.6 Hz, 1H), 3.26 (d, J=12.9 Hz,1H), 3.16-3.13 (m, 1H), 2.81-2.79 (m, 1H), 2.72-2.67 (m, 1H), 1.83 (brs, 1H), 1.45 (s, 9H).

Step D. tert-Butyl1-(2,3-difluorobenzyl)-5-oxo-4-(2,2,2-trifluoroethyl)-1,4-diazepan-6-ylcarbamate

A mixture of tert-butyl7-oxo-1-(2,2,2-trifluoroethyl)-1,4-diazepan-6-ylcarbamate (51 mg, 0.16mmol), 2,3-difluorobenzaldehyde (0.053 mL, 0.49 mmol), and sodiumcyanoborohydride (31 mg, 0.49 mmol) in methanol (5 mL) was adjusted topH 4 with acetic acid. After 0.5 h, saturated aqueous sodium bicarbonatewas added and the mixture was extracted with dichloromethane (3×). Thecombined organic extracts were dried over magnesium sulfate, filtered,and concentrated. Purification by silica gel chromatography [100%dichloromethane→95% dichloromethane/5% (10% ammoniumhydroxide/methanol)] gave the title compound (62 mg). MS 438 (M+1).

Step E:6-Amino-1-(2,3-difluorobenzyl)-4-(2,2,2-trifluoroethyl)-1,4-diazepan-5-one

Trifluoroacetic acid (2.5 mL) was added to a solution of tert-butyl1-(2,3-difluorobenzyl)-5-oxo-4-(2,2,2-trifluoroethyl)-1,4-diazepan-6-ylcarbamate(62 mg, 0.142 mmol) in dichloromethane (5 mL). After 1 h, the solutionwas concentrated. Saturated aqueous sodium bicarbonate solution wasadded and the mixture was extracted with dichloromethane (3×). Thecombined organic extracts were washed with saturated brine, dried overmagnesium sulfate, filtered and concentrated to give the title compound(45 mg). MS 338 (M+1).

Step F:N-[1-(2,3-Difluorobenzyl)-5-oxo-4-(2,2,2-trifluoroethyl)-1,4-diazepan-6-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide

Triethylamine (0.012 mL, 0.133 mmol) was added to a solution of6-amino-1-(2,3-difluorobenzyl)-4-(2,2,2-trifluoroethyl)-1,4-diazepan-5-one(45 mg, 0.133 mmol) and 4-nitrophenyl chloroformate (27 mg, 133 mmol) intetrahydrofuran (2.5 mL) at 0° C. After 1 h,2-oxo-1-(4-piperidinyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridinedihydrochloride (43 mg, 0.147 mmol) and triethylamine (0.048 mL, 0.532mmol) were added and the mixture allowed to warm to ambient temperature.After 18 h, the mixture was partitioned between ethyl acetate and water.The organic layer was washed with water (2×), saturated brine, driedover magnesium sulfate, filtered and concentrated. Purification bysilica gel chromatography [100% dichloromethane→92%dichloromethane/methanol (10% ammonium hydroxide/methanol)] gave thetitle compound (67 mg). MS 582.2262 (M+1). ¹H NMR (500 MHz, CDCl₃) δ8.77 (s, 1H), 8.03 (d, J=5.4 Hz, 1H), 7.31 (d, J=8.1 Hz, 1H), 7.27-7.24(m, 1H), 7.09-7.05 (m, 2H), 6.98 (dd, J=8.1, 5.4 Hz, 1H), 5.99 (d, J=4.9Hz, 1H), 4.91-4.88 (m, 1H), 4.57-4.50 (m, 1H), 4.25-4.16 (m, 3H),4.00-3.92 (m, 2H), 3.84 (dd, J=32.7, 14.2 Hz, 2H), 3.36-3.34 (m, 1H),3.20 (d, J=12.5 Hz, 1H), 2.99-2.91 (m, 3H), 2.44-2.37 (m, 2H), 2.31-2.18(m, 2H), 1.90 (d, J=11.0 Hz, 2H).

Essentially following the procedures outlined for the preparation ofExample 180, the Examples in Table E-7 were prepared. TABLE E-7

Example R² MS (M + 1) 181

546.2450 182 H 456.1983 183

590.2295

1. A compound of the Formula I:

wherein: A is a bond, C(R²)₂, O, S(O)_(m) or NR²; B is (C(R²)₂)_(n); R¹ is selected from: 1) H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃₋₆ cycloalkyl, and heterocycle, unsubstituted or substituted with one or more substituents independently selected from: a) C₁₋₆ alkyl, b) C₃₋₆ cycloalkyl, c) aryl, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R⁴, d) heteroaryl, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R⁴, e) heterocycle, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R⁴, f) (F)_(p)C₁₋₃ alkyl, g) halogen, h) OR⁴, i) O(CH₂)_(s)OR⁴, j) CO₂R⁴, k) (CO)NR¹⁰R¹¹, l) O(CO)NR¹⁰R¹¹, m) N(R⁴)(CO)NR¹⁰R¹¹, n) N(R¹¹)(CO)R¹¹, o) N(R¹⁰)(CO)OR¹¹, p) SO₂NR¹⁰R¹¹, q) N(R¹⁰)SO₂R¹¹, r) S(O)_(m)R¹⁰, s) CN, t) NR¹⁰R¹¹, u) N(R¹⁰)(CO)NR⁴R¹¹ and, v) O(CO)R⁴; 2) aryl or heteroaryl, unsubstituted or substituted with one or more substituents independently selected from: a) C₁₋₆ alkyl, b) C₃₋₆ cycloalkyl, c) aryl, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R⁴, d) heteroaryl, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R⁴, e) heterocycle, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R⁴, f) (F)_(p)C₁₋₃ alkyl, g) halogen, h) OR⁴, i) O(CH₂)_(s)OR⁴, j) CO₂R⁴, k) (CO)NR¹⁰R¹¹, l) O(CO)NR¹⁰R¹¹, m) N(R⁴)(CO)NR¹⁰R¹¹, n) N(R¹⁰)(CO)R¹¹, o) N(R¹⁰)(CO)OR¹¹, p) SO₂NR¹⁰R¹¹, q) N(R¹⁰)SO₂R¹¹, r) S(O)_(m)R¹⁰, s) CN, t) NR¹⁰R¹¹, u) N(R¹⁰)(CO)NR⁴R¹¹ and, v) O(CO)R⁴; R² is independently selected from: 1) H, C₀-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃₋₆ cycloalkyl and heterocycle, unsubstituted or substituted with one or more substituents independently selected from: a) C₁₋₆ alkyl, b) C₃₋₆ cycloalkyl, c) aryl, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R⁴, d) heteroaryl, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R⁴, e) heterocycle, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R⁴, f) (F)_(p)C₁₋₃ alkyl, g) halogen, h) OR⁴, i) O(CH₂)_(s)OR⁴, j) CO₂R⁴, k) (CO)NR¹⁰R¹¹, l) O(CO)NR¹⁰R¹¹, m) N(R⁴)(CO)NR¹⁰R¹¹, n) N(R¹⁰)(CO)R¹¹, o) N(R¹⁰)(CO)OR¹¹, p) SO₂NR¹⁰R¹¹, q) N(R¹⁰)SO₂R¹¹, r) S(O)_(m)R¹⁰, s) CN, t) NR¹⁰R¹¹, u) N(R¹⁰)(CO)NR⁴R¹¹ and, v) O(CO)R⁴; 2) aryl or heteroaryl, unsubstituted or substituted with one or more substituents independently selected from: a) C₁₋₆ alkyl, b) C₃₋₆ cycloalkyl, c) aryl, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R⁴, d) heteroaryl, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R⁴, e) heterocycle, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R⁴, f) (F)_(p)C₁₋₃ alkyl, g) halogen, h) OR⁴, i) O(CH₂)_(s)OR⁴, j) CO₂R⁴, k) (CO)NR¹⁰R¹¹, l) O(CO)NR¹⁰R¹¹, m) N(R⁴)(CO)NR¹⁰R¹¹, n) N(R¹⁰)(CO)R¹¹, o) N(R¹⁰)(CO)OR¹¹, p) SO₂NR¹⁰R¹¹, q) N(R¹⁰)SO₂R¹¹, r) S(O)_(m)R¹⁰, s) CN, t) NR¹⁰R¹¹, u) N(R¹⁰)(CO)NR⁴R¹¹ and, v) O(CO)R⁴, or, any two independent R² on the same or adjacent atoms may be joined together to form a ring selected from cyclobutyl, cyclopentenyl, cyclopentyl, cyclohexenyl, cyclohexyl, phenyl, naphthyl, thienyl, thiazolyl, thiazolinyl, oxazolyl, oxazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrimidyl, pyrazinyl, pyrrolyl, pyrrolinyl, morpholinyl, thiomorpholine, thiomorpholine S-oxide, thiomorpholine S-dioxide, azetidinyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridyl, furanyl, dihydrofuranyl, dihydropyranyl and piperazinyl; R¹⁰ and R¹¹ are independently selected from: H, C₁₋₆ alkyl, (F)_(p)C₁₆ alkyl, C₃₋₆ cycloalkyl, aryl, heteroaryl, and benzyl, unsubstituted or substituted with halogen, hydroxy or C₁-C₆ alkoxy, where R¹⁰ and R¹¹ may be joined together to form a ring selected from: azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, which is unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R⁴; R⁴ is independently selected from: H, C₁₋₆ alkyl, (F)_(p)C₁₋₆ alkyl, C₃₋₆ cycloalkyl, aryl, heteroaryl and benzyl, unsubstituted or substituted with halogen, hydroxy or C₁-C₆ alkoxy; W is O, NR⁴ or C(R⁴)₂; X is C or S; Y is O, (R⁴)₂, NCN, NSO₂CH₃, NCONH₂, or Y is O₂ when X is S; R⁶ is independently selected from H and: a) C₁₋₆ alkyl, b) C₃₋₆ cycloalkyl, c) aryl, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R⁴, d) heteroaryl, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R⁴, e) heterocycle, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R⁴, f) (F)_(p)C₁₋₃ alkyl, g) halogen, h) OR⁴, i) O(CH₂)_(s)OR⁴, j) CO₂R⁴, k) (CO)NR¹⁰R¹¹, l) O(CO)NR¹⁰R¹¹, m) N(R⁴)(CO)NR¹⁰R¹¹, n) N(R¹⁰)(CO)R¹¹, o) N(R¹⁰)(CO)OR¹¹, p) SO₂NR¹⁰R¹¹, q) N(R¹⁰)SO₂R¹¹, r) S(O)_(m)R¹⁰, s) CN, t) NR¹⁰R¹¹, u) N(R¹⁰)(CO)NR⁴R¹¹ and, v) O(CO)R⁴; G-J is selected from: N, N—C(R⁵)₂, C═C(R⁵), C═N; C(R⁵), C(R⁵)—C(R⁵)₂, C(R⁵)—C(R⁵)₂—C(R⁵)₂, C═C(R⁵)—C(R⁵)₂, C(R⁵)—C(R⁵)═C(R⁵), C(R⁵)—C(R⁵)₂—N(R⁵), C═C(R⁵)—N(R⁵), C(R⁵)—C(R⁵)═N, C(R⁵)—N(R⁵)—C(R⁵)₂, C═N—C(R⁵)₂, C(R⁵)—N═C(R⁵), C(R⁵)—N(R⁵)—N(R⁵), C═N—N(R⁵), N—C(R⁵)₂—C(R⁵)₂, N—C(R⁵)═C(R⁵), N—C(R⁵)₂—N(R⁵), N—C(R⁵)═N, N—N(R⁵)—C(R⁵)₂ and N—N═C(R⁵); Q, T, U and V are each independently carbon or nitrogen wherein at least one but no more than three of Q, T, U and V are nitrogen, of which one may be optionally an N-oxide, and wherein when any of Q, T, U, or V is carbon it is unsubstituted or substituted where the substituents are independently selected from R⁶; R⁵ is independently selected from H, substituted or unsubstituted C₁-C₃ alkyl, CN, OR⁴, N(R⁴)₂ and CO₂R⁴; R³ is independently selected from H, substituted or unsubstituted C₁-C₃ alkyl, F, CN and CO₂R⁴; p is 0 to 2q+1, for a substituent with q carbons; m is 0, 1 or 2; n is 0 or 1; s is 1, 2 or 3; and pharmaceutically acceptable salts and individual diastereomers thereof.
 2. The compound of claim 1 of the Formula Ia:

wherein: A is a bond, C(R²)₂, O, S(O)_(m) or NR²; B is (C(R²)₂)_(n); Y is O or NCN; and n is 0 or 1; and pharmaceutically acceptable salts and individual stereoisomers thereof.
 3. The compound of claim 1 of the Formula Ib:

wherein: A is a bond, C(R²)₂, O, S(O)_(m) or NR²; B is (C(R²)₂)_(n); and n is 0 or 1; and pharmaceutically acceptable salts and individual stereoisomers thereof.
 4. The compound of claim 1 of the Formula Ic:

and pharmaceutically acceptable salts and individual stereoisomers thereof.
 5. The compound of claim 1 of the Formula Id:

wherein: A is C(R²)₂, O, S(O)_(m) or NR²; and pharmaceutically acceptable salts and individual stereoisomers thereof.
 6. The compound of claim 1 of the Formula Ie:

wherein: A is C(R²)₂, O, S(O)_(m) or NR²; and pharmaceutically acceptable salts and individual stereoisomers thereof.
 7. The compound of claim 1, wherein: R¹ is selected from: 1) H, C₁-C₆ alkyl, C₃₋₆ cycloalkyl and heterocycle, unsubstituted or substituted with one or more substituents independently selected from: a) C₁₋₆ alkyl, b) C₃₋₆ cycloalkyl, c) aryl, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R⁴, d) heteroaryl, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R⁴, e) heterocycle, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R⁴, f) (F)_(p)C₁₋₃ alkyl, g) halogen, h) OR⁴, i) O(CH₂)_(s)OR⁴, j) CO₂R⁴, k) CN, l) NR¹⁰R¹¹, and m) O(CO)R⁴; and 2) aryl or heteroaryl, unsubstituted or substituted with one or more substituents independently selected from: a) C₁₋₆ alkyl, b) C₃₋₆ cycloalkyl, c) (F)_(p)C₁₋₃ alkyl, d) halogen, e) OR⁴, f) CO₂R⁴, g) (CO)NR¹⁰R¹¹, h) SO₂NR¹⁰R¹¹, i) N(R¹⁰)SO₂R¹¹, j) S(O)_(m)R⁴, k) CN and l) NR¹⁰R¹¹, and m) O(CO)R⁴; and R² is selected from: 1) H, C₁-C₆ alkyl, C₂-C₆ alkynyl, C₃₋₆ cycloalkyl and heterocycle, unsubstituted or substituted with one or more substituents independently selected from: a) C₁₋₆ alkyl, b) C₃₋₆ cycloalkyl, c) aryl, unsubstituted or substituted with 1-5 sustituents where the substituents are independently selected from R⁴, d) heteroaryl, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R⁴, e) heterocycle, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R⁴, f) (F)_(p)C₁₋₃ alkyl, g) halogen, h) OR⁴, i) O(CH₂)_(s)OR⁴, j) CO₂R⁴, k) S(O)_(m)R⁴, l) CN, m) NR¹⁰R¹¹, and n) O(CO)R⁴; and 2) aryl or heteroaryl, unsubstituted or substituted with one more substituents independently selected from: a) C₁₋₆ alkyl, b) C₃₋₆ cycloalkyl, c) (F)_(p)C₁₋₃ alkyl, d) halogen, e) OR⁴, f) CO₂R⁴, g) (CO)NR¹⁰R¹¹, h) SO₂NR¹⁰R¹¹, i) N(R¹⁰)SO₂R¹¹, j) S(O)_(m)R⁴, k) CN, l) NR¹⁰R¹¹, m) O(CO)R⁴, or, any two independent R² on the same or adjacent atoms may be joined together to form a ring selected from cyclobutyl, cyclopentenyl, cyclopentyl, cyclohexenyl, cyclohexyl, phenyl, naphthyl, thienyl, thiazolyl, thiazolinyl, oxazolyl, oxazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrimidyl, pyrazinyl, pyrrolyl, pyrrolinyl, morpholinyl, thiomorpholine, thiomorpholine S-oxide, thiomorpholine S-dioxide, azetidinyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridyl, furanyl, dihydrofuranyl, dihydropyranyl and piperazinyl; G-J is selected from: N, N—C(R⁵)₂, C═C(R⁵), C═N, C═C(R⁵)—C(R⁵), C(R⁵)—C(R⁵)═C(R⁵), N—C(R⁵)₂—C(R⁵)₂ and N—C(R⁵)═C(R⁵); R⁶ is independently selected from H and: a) C₁₋₆ alkyl, b) C₃₋₆ cycloalkyl, c) (F)_(p)C₁₋₃ alkyl, d) halogen, e) OR⁴, f) CO₂R⁴, g) (CO)NR¹⁰R¹¹, h) SO₂NR¹⁰R¹¹, i) N(R¹⁰)SO₂R¹¹, j) S(O)_(m)R⁴, k) CN, l) NR¹⁰R¹¹, and m) O(CO)R⁴; and pharmaceutically acceptable salts and individual stereoisomers thereof.
 8. The compound of claim 7 of the Formula Ia:

wherein: A is a bond, C(R²)₂, O, S(O)_(m) or NR²; B is (C(R²)₂)_(n); Y is O or NCN; and n is 0 or 1; and pharmaceutically acceptable salts and individual stereoisomers thereof.
 9. The compound of claim 7 of the Formula Ib:

wherein: A is a bond, C(R²)₂, O, S(O)_(m) or NR²; B is (C(R²)₂)_(n); and n is 0 or 1; and pharmaceutically acceptable salts and individual stereoisomers thereof.
 10. The compound of claim 7 of the Formula Ic:

and pharmaceutically acceptable salts and individual stereoisomers thereof.
 11. The compound of claim 7 of the Formula Id:

wherein: A is C(R²)₂, O, S(O)_(m) or NR²; and pharmaceutically acceptable salts and individual stereoisomers thereof.
 12. The compound of claim 7 of the Formula Ie:

wherein: A is C(R²)₂, O, S(O)_(m) or NR²; and pharmaceutically acceptable salts and individual stereoisomers thereof.
 13. The compound of claim 1, wherein: R is selected from: 1) H, C₁-C₆ alkyl, C₃₋₆ cycloalkyl and heterocycle, unsubstituted or substituted with one or more substituents independently selected from: a) C₁₋₆ alkyl, b) C₃₋₆ cycloalkyl, c) phenyl, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R⁴, d) heteroaryl, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R⁴, and where heteroaryl is selected from: imidazole, isoxazole, oxazole, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, and thiazole; e) heterocycle, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R⁴, and where heterocycle is selected from: azetidine, dioxane, dioxolane, morpholine, oxetane, piperazine, piperidine, pyrrolidine, tetrahydrofuran, and tetrahydropyran; f) (F)_(p)C₁₋₃ alkyl, g) halogen, h) OR⁴, i) O(CH₂)_(s)OR⁴, j) CO₂R⁴, k) CN, and l) NR¹⁰R¹¹; and 2) aryl or heteroaryl, selected from: phenyl, imidazole, isoxazole, oxazole, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, and thiazole; unsubstituted or substituted with one or more substituents independently selected from: a) C₁₋₆ alkyl, b) C₃₋₆ cycloalkyl, c) (F)_(p)C₁₋₃ alkyl, d) halogen, e) OR⁴, f) CO₂R⁴, g) (CO)NR¹⁰R¹¹, h) SO₂NR¹⁰R¹¹, i) N(R¹⁰)SO₂R¹¹, j) S(O)_(m)R⁴, k) CN and l) NR¹⁰R¹¹; R² is selected from: 1) H, C₀-C₆ alkyl, C₃₋₆ cycloalkyl and heterocycle, unsubstituted or substituted with one or more substituents independently selected from: a) C₁₋₆ alkyl, b) C₃₋₆ cycloalkyl, c) phenyl, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R⁴, d) heteroaryl, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R⁴, and where heteroaryl is selected from: benzimidazole, benzothiophene, furan, imidazole, indole, isoxazole, oxazole, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, thiazole, thiophene, and triazole; e) heterocycle, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R⁴, and where heterocycle is selected from: azetidine, imidazolidine, imidazoline, isoxazoline, isoxazolidine, morpholine, oxazoline, oxazolidine, oxetane, pyrazolidine, pyrazoline, pyrroline, tetrahydrofuran, tetrahydropyran, thiazoline, and thiazolidine; f) (F)_(p)C₁₋₃ alkyl, g) halogen, h) OR⁴, i) O(CH₂)_(s)OR⁴, j) CO₂R⁴, k) CN, and l) NR¹⁰R¹¹; and 2) aryl or heteroaryl, selected from: phenyl, benzimidazole, benzothiophene, furan, imidazole, indole, isoxazole, oxazole, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, thiazole, thiophene, and triazole; unsubstituted or substituted with one or more substituents independently selected from: a) C₁₋₆ alkyl, b) C₃₋₆ cycloalkyl, c) (F)_(p)C₁₋₃ alkyl, d) halogen, e) OR⁴, f) CO₂R⁴, g) (CO)NR¹⁰R¹¹, h) SO₂NR¹⁰R¹¹, i) N(R¹⁰)SO₂R¹¹, j) S(O)_(m)R⁴, k) CN and l) NR¹⁰R¹¹, or, any two independent R² on the same or adjacent atoms may be joined together to form a ring selected from cyclobutyl, cyclopentenyl, cyclopentyl, cyclohexenyl, cyclohexyl, phenyl, naphthyl, thienyl, thiazolyl, thiazolinyl, oxazolyl, oxazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrimidyl, pyrazinyl, pyrrolyl, pyrrolinyl, morpholinyl, thiomorpholine, thiomorpholine S-oxide, thiomorpholine S-dioxide, azetidinyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridyl, furanyl, dihydrofuranyl, dihydropyranyl and piperazinyl; R¹⁰ and R¹¹ are independently selected from: H, C₁₋₆ alkyl, (F)_(p)C₁₋₆ alkyl, C₃₋₆ cycloalkyl, aryl, heteroaryl and benzyl, unsubstituted or substituted with halogen, hydroxy or C₁-C₆ alkoxy, where R¹⁰ and R¹¹ may be joined together to form a ring selected from: azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl, which is unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R⁴; R⁴ is independently selected from: H, C₁₋₆ alkyl, (F)_(p)C₁₆ alkyl, C₃₋₆ cycloalkyl, aryl, heteroaryl and phenyl, unsubstituted or substituted with hydroxy or C₁-C₆ alkoxy; W is NR⁴ or C(R⁴)₂; G-J is N and Q-T-U-V is N═C(R⁶)—C(R⁶)═C(R⁶), G-J is N and Q-T-U-V is C(R⁶)═N—C(R⁶)═C(R⁶), G-J is N and Q-T-U-V is C(R⁶)═C(R⁶)—N═C(R⁶), G-J is N and Q-T-U-V is C(R⁶)═C(R⁶)—C(R⁶)═N, G-J is N and Q-T-U-V is C(R⁶)═C(R⁶)—N═N, G-J is N and Q-T-U-V is C(R⁶)═N—C(R⁶)═N, G-J is N and Q-T-U-V is N═C(R⁶)—C(R⁶)═N, G-J is N—C(R⁵)₂ and Q-T-U-V is C(R⁶)═C(R⁶)—C(R⁶)═N, G-J is N—C(R⁵)₂ and Q-T-U-V is C(R⁶)═N—C(R⁶)═C(R⁶), G-J is C═C(R⁵) and Q-T-U-V is C(R⁶)═C(R⁶)—C(R⁶)═N, G-J is C═C(R⁵) and Q-T-U-V is C(R⁶)═N—C(R⁶)═C(R⁶), G-J is C═N and Q-T-U-V is C(R⁶)═C(R⁶)—C(R⁶)═N, G-J is C═N and Q-T-U-V is C(R⁶)═N—C(R⁶)═C(R⁶), G-J is N—C(R⁵)₂—C(R⁵)₂ and Q-T-U-V is C(R⁶)═C(R⁶)—C(R⁶)═N, or G-J is N—C(R⁵)₂—C(R⁵)₂ and Q-T-U-V is C(R⁶)═N—C(R⁶)═C(R⁶), R⁶ is independently selected from H and: a) C₁₋₆ alkyl, b) C₃₋₆ cycloalkyl, c) (F)_(p)C₁₋₃ alkyl, d) halogen, e) OR⁴, f) CO₂R⁴, g) (CO)NR¹⁰R¹¹, h) SO₂NR¹⁰R¹¹, i) N(R¹⁰)SO₂R¹¹, j) S(O)_(m)R⁴, k) CN and i) NR¹⁰R¹¹; and pharmaceutically acceptable salts and individual stereoisomers thereof.
 14. The compound of claim 13 of the Formula Ia:

and pharmaceutically acceptable salts and individual stereoisomers thereof.
 15. The compound of claim 13 of the Formula Ib:

and pharmaceutically acceptable salts and individual stereoisomers thereof.
 16. The compound of claim 13 of the Formula Ic:

and pharmaceutically acceptable salts and individual stereoisomers thereof.
 17. The compound of claim 13 of the Formula Id:

and pharmaceutically acceptable salts and individual stereoisomers thereof.
 18. The compound of claim 13 of the Formula Ie:

and pharmaceutically acceptable salts and individual stereoisomers thereof.
 19. A compound of the Formula II:

wherein: B is independently (C(R²)₂)_(n); R¹ is selected from: 1) H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃₋₆ cycloalkyl, and heterocycle, unsubstituted or substituted with one or more substituents independently selected from: a) C₁₋₆ alkyl, b) C₃₋₆ cycloalkyl, c) aryl, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R⁴, d) heteroaryl, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R⁴, e) heterocycle, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R⁴, f) (F)_(p)C₁₋₃ alkyl, g) halogen, h) OR⁴, i) O(CH₂)_(s)OR⁴, j) CO₂R⁴, k) (CO)NR¹⁰R¹¹, l) O(CO)NR¹⁰R¹¹, m) N(R⁴)(CO)NR¹⁰R¹¹, n) N(R¹⁰)(CO)R¹¹, o) N(R¹⁰)(CO)OR¹¹, p) SO₂NR¹⁰R¹¹, q) N(R¹⁰)SO₂R¹¹, r) S(O)_(m)R¹⁰, s) CN, t) NR¹⁰R¹¹, and u) N(R¹⁰)(CO)NR⁴R¹¹; and, 2) aryl or heteroaryl, unsubstituted or substituted with one or more substituents independently selected from: a) C₁₋₆ alkyl, b) C₃₋₆ cycloalkyl, c) aryl, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R⁴, d) heteroaryl, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R⁴, e) heterocycle, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R⁴, f) (F)_(p)C₁₋₃ alkyl, g) halogen, h) OR⁴, i) O(CH₂)_(s)OR⁴, j) CO₂R⁴, k) (CO)NR¹⁰R¹¹, l) O(CO)NR¹⁰R¹¹, m) N(R⁴)(CO)NR¹⁰R¹¹, n) N(R¹⁰)(CO)R¹¹, o) N(R¹⁰)(CO)OR¹¹, p) SO₂NR¹⁰R¹¹, q) N(R¹⁰)SO₂R¹¹, r) S(O)_(m)R¹⁰, s) CN, w) NR¹⁰R¹¹, and x) N(R¹⁰)(CO)NR⁴R¹¹; R² is independently selected from: 1) H, C₀-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃₋₆ cycloalkyl and heterocycle, unsubstituted or substituted with one or more substituents independently selected from: a) C₁₋₆ alkyl, b) C₃₋₆ cycloalkyl, c) aryl, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R⁴, d) heteroaryl, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R⁴, e) heterocycle, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R⁴, f) (F)_(p)C₁₋₃ alkyl, g) halogen, h) OR⁴, i) O(CH₂)_(s)OR⁴, j) CO₂R⁴, k) (CO)NR¹⁰R¹¹, l) O(CO)NR¹⁰R¹¹, m) N(R⁴)(CO)NR¹⁰R¹¹, n) N(R¹⁰)(CO)R¹¹, o) N(R¹⁰)(CO)OR¹¹, p) SO₂NR¹⁰R¹¹, q) N(R¹⁰)SO₂R¹¹, r) S(O)_(m)R¹⁰, s) CN, t) NR¹⁰R¹¹, and u) N(R¹⁰)(CO)NR⁴R¹¹; and, 2) aryl or heteroaryl, unsubstituted or substituted with one or more substituents independently selected from: a) C₁₋₆ alkyl, b) C₃₋₆ cycloalkyl, c) aryl, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R⁴, d) heteroaryl, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R⁴, e) heterocycle, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R⁴, f) (F)_(p)C₁₋₃ alkyl, g) halogen, h) OR⁴, i) O(CH₂)_(s)OR⁴, j) CO₂R⁴, k) (CO)NR¹⁰R¹¹, l) O(CO)NR¹⁰R¹¹, m) N(R⁴)(CO)NR¹⁰R¹¹, n) N(R¹⁰)(CO)R¹¹, o) N(R¹⁰)(CO)OR¹¹, p) SO₂NR¹⁰R¹¹, q) N(R¹⁰)SO₂R¹¹, r) S(O)_(m)R¹⁰, s) CN, t) NR¹⁰R¹¹ and u) N(R¹⁰)(CO)NR⁴R¹¹; R¹⁰ and R¹¹ are independently selected from: H, C₁₋₆ alkyl, (F)_(p)C₁₆ alkyl, C₃₋₆ cycloalkyl, aryl, heteroaryl, and benzyl, unsubstituted or substituted with halogen, hydroxy or C₁-C₆ alkoxy, where R¹⁰ and R¹¹ may be joined together to form a ring selected from: azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, which is unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R⁴; R⁴ is independently selected from: H, C₁₋₆ alkyl, (F)_(p)C₁₋₆ alkyl, C₃₋₆ cycloalkyl, aryl, heteroaryl and benzyl, unsubstituted or substituted with halogen, hydroxy or C₁-C₆ alkoxy; W is O, NR⁴ or C(R⁴)₂; X is C or S; Y is O, (R⁴)₂, NCN, NSO₂CH₃, NCONH₂, or Y is O₂ when X is S; R⁶ is independently selected from H and: a) C₁₋₆ alkyl, b) C₃₋₆ cycloalkyl, c) aryl, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R⁴, d) heteroaryl, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R⁴, e) heterocycle, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R⁴, f) (F)_(p)C₁₋₃ alkyl, g) halogen, h) OR⁴, i) O(CH₂)_(s)OR⁴, j) CO₂R⁴, k) (CO)NR¹⁰R¹¹, l) O(CO)NR¹⁰R¹¹, m) N(R⁴)(CO)NR¹⁰R¹¹, n) N(R¹⁰)(CO)R¹¹, o) N(R¹⁰)(CO)OR¹¹, p) SO₂NR¹⁰R¹¹, q) N(R¹⁰)SO₂R¹¹, r) S(O)_(m)R¹⁰, s) CN, t) NR¹⁰R¹¹ and u) N(R¹⁰)(CO)NR⁴R₁₁; G-J is selected from: N, N—C(R⁵)₂, C═C(R⁵), C═N; C(R⁵), C(R⁵)—C(R⁵)₂, C(R⁵)—C(R⁵)₂—C(R⁵)₂, C═C(R⁵)—C(R⁵)₂, C(R⁵)—C(R⁵)═C(R⁵), C(R⁵)—C(R⁵)₂—N(R⁵), C═C(R⁵)—N(R⁵), C(R⁵)—C(R⁵)═N, C(R⁵)—N(R⁵)—C(R⁵)₂, C═N—C(R⁵)₂, C(R⁵)—N═C(R⁵), C(R⁵)—N(R⁵)—N(R⁵), C═N—N(R⁵), N—C(R⁵)₂—C(R⁵)₂, N—C(R⁵)═C(R⁵), N—C(R⁵)₂-N(R⁵), N—C(R⁵)═N, N—N(R⁵)—C(R⁵)₂ and N—N═C(R⁵); Q, T, U and V are each independently carbon or nitrogen wherein at least one but no more than three of Q, T, U and V are nitrogen, and wherein when any of Q, T, U, or V is carbon it is unsubstituted or substituted where the substituents are independently selected from R⁶; R⁵ is independently selected from H, substituted or unsubstituted C₁-C₃ alkyl, CN, OR⁴, N(R⁴)₂ and CO₂R⁴; R³ is independently selected from H, substituted or unsubstituted C₁-C₃ alkyl, F, CN and CO₂R⁴; p is 0 to 2q+1, for a substituent with q carbons; m is 0, 1 or 2; n is 0 or 1; s is 1, 2 or 3; and pharmaceutically acceptable salts and individual diastereomers thereof.
 20. A compound selected from:

and pharmaceutically acceptable salts and individual stereoisomers thereof.
 21. A compound of the formula:

wherein the configuration of the C-3 carbon, the configuration of the C-6 carbon, and R¹ are selected from a single row in the following table: C-3 C-6 R¹ R S H R R H R S CH₃ R S CH₂CH₃ R S CH₂CF₃ R S CH₂CO₂CH₃ R S CH₂CO₂H R S (CH₂)₂OCH₂CH₃ R S CH₂CN R S (CH₂)₂OH R S

R S

R S CH₂CH₂F R S CH₂CHF₂ R S CH₂CHCF₂ R S

R S

R S

R S

R S

R S

R S

R S

R S

R S (CH₂)₂OCF₃ R S

R S

R S

R S

R S

R S

R S Ph R S

and pharmaceutically acceptable salts and individual stereoisomers thereof.
 22. A compound of the formula:

wherein the configuration of the C-6 carbon, and R¹ and R² are selected from a single row in the following table: C-6 R¹ R² R or S H

S H

R or S H

R or S H

R or S H

R H

R or S H

R or S H

R or S H

R or S

S

S

R

R or S H

R or S H

R or S H

R or S H

R or S H

R or S H

R or S H

S H

R or S H

R or S H

R or S H

R or S H

R or S H

R or S H

S Et

S CH₂CH₂F

S CH₂CH₂OMe

R or S Et

R or S Me

S Me

S Et

R or S Et

R or S CH₂CF₃

and pharmaceutically acceptable salts and individual stereoisomers thereof.
 23. A compound of the formula:

wherein the configuration of the C-3 carbon, the configuration of the C-6 carbon, and R¹ are selected from a single row in the following table: C-3 C-6 R¹ R S

S R

R R

S S

and pharmaceutically acceptable salts and individual stereoisomers thereof.
 24. A compound of the formula:

wherein R is selected from:

and pharmaceutically acceptable salts and individual stereoisomers thereof.
 25. A compound of the formula:

wherein R is selected from:

and pharmaceutically acceptable salts and individual stereoisomers thereof.
 26. A compound of the formula:

wherein the configuration of the C-3 carbon, the configuration of the C-5 carbon, R¹ and R² are selected from a single row in the following table: C-3 C-5 R¹ R² R or S R or S CH₂CH₂OCH₃

R or S R or S CH₃

R or S R or S CH₃

R or S R or S CH₂CF₃

R or S R or S CH₂CF₃

R R CH₂CF₃

R S CH₂CF₃

S R CH₂CF₃

S S CH₂CF₃

and pharmaceutically acceptable salts and individual stereoisomers thereof.
 27. A compound of the formula:

wherein R² is selected from:

and pharmaceutically acceptable salts and individual stereoisomers thereof.
 28. A pharmaceutical composition which comprises an inert carrier and the compound of claim
 1. 29. The use of the compound of claim 1 for the preparation of a medicament useful in the treatment of headache, migraine or cluster headache. 